Activation of carbonyl beta-carbons for chemical transformations

ABSTRACT

The present invention relates to a method for synthesizing a compound of Formula (I)as defined herein, comprising: (i) activating a compound of Formula (II)as defined herein, by reacting said compound of Formula (II) with a compound of Formula (III)as defined herein, in the presence of a base, to obtain a compound of Formula (IV)as defined herein; and (ii) reacting the compound of Formula (IV) with an electrophile to obtain the compound of Formula (I). The present invention further relates to the organocatalysts used in the described methods and their respective uses.

FIELD OF THE INVENTION

The present invention relates to the fields of organocatalyticactivation of carbonyl β-carbons to synthesize β-carbon nucleophiles.The present invention is further directed to the organocatalysts usedherein and their respective uses.

BACKGROUND

Carbonyl compounds, such as esters, ketones, and aldehydes are essentialbuilding blocks in organic chemistry, particularly in the field ofpharmaceuticals, fine chemicals, and materials. Therefore, carbonylcompounds are involved in different multistage chemical synthesis. Theactivation of the α-carbons of carbonyl compounds in order to generateenolate equivalents as nucleophiles is one of the most powerfulstrategies and commonly used synthesis in organic chemistry includingaldol reactions and Mannich reactions. The functionalization of theseα-carbons is well known and can be realized via metal-based or organiccatalysts or reagents. The most relevant method is directinggroup-assisted metal insertion and C—H bond activation involving theester β-carbons using palladium-based transition metal catalysts. Asstarting material, typically the corresponding α,β-unsaturated carbonylcompounds are used. In contrast herein, the β-carbon of saturatedcarbonyl compounds is considered to be rather inert. Despite of thefundamental and practical values, direct transformation of β-carbons ofsaturated carbonyl compounds to nucleophiles is still challenging.

Hence, there is a need in the art for direct activation of carbonylβ-carbons for chemical transformations.

SUMMARY OF THE INVENTION

The present invention provides a method for synthesizing a compound ofFormula (I)

wherein

a single or a double bond, wherein if it is a double bond n is 1 and ifit is a single bond n is 2;

each R₁ and R₂ is independently selected from the group consisting ofhydrogen, halogen, —OH, —OOH, —NH₂, —NO₂, —ONO₂, —CHO, —CN, —CNOH,—COOH, —SH, —OSH, —CSSH, —SCN, —SO₂OH, —CONH₂, —NH—NH₂, —NC, —CSH, orany organic moiety;

B is an electrophilic group; and

NHC⁺ is

comprising:(i) activating a compound of Formula (II)

wherein

LG is a leaving group;

by reacting said compound of Formula (II) with a compound of Formula(III) in the presence of a base

wherein

R₃, R₄, and R₅ are independently from each other selected from the groupconsisting of hydrogen, halogen, —OH, —OOH, —NH₂, —NO₂, —ONO₂, —CHO,—CN, —CNOH, —COOH, —SH, —OSH, —CSSH, —SCN, —SO₂OH, —CONH₂, —NH—NH₂, —NC,—CSH, or any organic moiety; to obtain a compound of Formula (IV)

and(ii) reacting the compound of Formula (IV) with an electrophile toobtain the compound of Formula (I).

In another aspect the present invention is directed to compounds ofFormulae (VI) and (VII)

wherein R₃, R₄, R₅, and R₆ are independently from each other selectedfrom the group consisting of hydrogen, halogen, —OH, —OOH, —NH₂, —NO₂,—ONO₂, —CHO, —CN, —CNOH, —COOH, —SH, —OSH, —CSSH, —SCN, —SO₂OH, —CONH₂,—NH—NH₂, —NC, —CSH, or any organic moiety.

In a still further aspect the present invention relates to the use ofcompounds of Formulae (VI) and (VII) for activating a compound ofFormula (II).

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention is based on the inventors' surprising finding thatthe β-carbon of a compound of Formula (II) can be activated to transformthe compound into a nucleophilic compound of Formula (IV) byorganocatalytic activation with a triazol carbene compound of Formula(III) and deprotonation with a base. Without wishing to be bound to anyparticular theory, it is believed that due to the electron-withdrawingability of the NHC⁺ moiety of Formula (III) and the conjugated nature ofthe compound of formula (IV), the proton(s) attached to the β-carbonbecome acidic. The obtained nucleophilic compound of Formula (IV) canthen further be reacted with an electrophile in order to synthesize acompound of Formula (I).

To obtain β-carbon functionalization, typically the correspondingα,β-unsaturated carbonyl compound is used which is subsequentlytransformed into the desired nucleophile by, e.g., directinggroup-assisted transition metal insertion using palladium and C—H bondactivation involving the β-carbons. When the saturated compound is thestarting material, a further synthetic step is required for convertingthe saturated carbonyl compound into the corresponding α,β-unsaturatedcompound. Thus, to functionalize the β-carbon additional synthetic stepsinvolving additional chemicals are necessary and, as a result,complexity of the synthesis procedure and costs are increased.

In contrast to the existing approaches, the present invention provides acost-effective and less complex strategy for the direct activation ofβ-carbons of carbonyl compounds without the need for additionalsynthetic steps and chemicals. The subsequent reaction of the compoundof Formula (IV) with an electrophile of interest to yield the desiredcompound of Formula (I) advantageously provides for high product yieldsand high selectivity, in particular with respect to enantiomeric ratios.

The inventive synthesis can be conducted at ambient conditions and as asimple one-pot synthesis without purification steps between thesynthesis of the compound of Formula (IV) and the subsequent synthesisof the compound of Formula (I).

Based on this finding, in a first aspect the present invention thusrelates to a method for synthesizing a compound of Formula (I)

wherein

a single or a double bond, wherein if it is a double bond n is 1 and ifit is a single bond n is 2;

each R₁ and R₂ is independently selected from the group consisting ofhydrogen, halogen, —OH, —OOH, —NH₂, —NO₂, —ONO₂, —CHO, —CN, —CNOH,—COOH, —SH, —OSH, —CSSH, —SCN, —SO₂OH, —CONH₂, —NH—NH₂, —NC, —CSH, orany organic moiety;

B is an electrophilic group; and

NHC⁺ is

comprising:(i) activating a compound of Formula (II)

wherein

LG is a leaving group;

by reacting said compound of Formula (II) with a compound of Formula(III) in the presence of a base

wherein

R₃, R₄, and R₅ are independently from each other hydrogen, halogen, —OH,—OOH, —NH₂, —NO₂, —ONO₂, —CHO, —CN, —CNOH, —COOH, —SH, —OSH, —CSSH,—SCN, —SO₂OH, —CONH₂, —NH—NH₂, —NC, —CSH, or any organic moiety;

to obtain a compound of Formula (IV)

and(ii) reacting the compound of Formula (IV) with an electrophile toobtain the compound of Formula (I).

In a preferred embodiment, the compound of Formula (I) can be asaturated carbonyl compound or its corresponding α,β-unsaturatedcompound. Preferably, the compound of Formula (I) is a saturatedcarbonyl compound meaning that the bond between the carbon atoms towhich R₁ and R₂ are attached to is a single bond and n is 2.Consequently, the α- and β-carbon atom bear two R₁ and R₂ moieties,respectively. The two R₁ moieties can be selected independently fromeach other. In other words, the first R₁ moiety can be different fromthe second R₁ moiety. The same applies for the R₂ moiety.

The term “any organic moiety” as used herein refers to carbon-containingmoieties. These moieties can be linear or branched, substituted orunsubstituted, and are preferably derived from hydrocarbons, typicallyby substitution of one or more hydrogen or carbon atoms by other atoms,such as oxygen, nitrogen, sulfur, phosphorous, or functional groups thatcontain oxygen, nitrogen, sulfur, phosphorous. The organic moiety cancomprise any number of carbon atoms, for example up to up to 5000 ormore (typically in case of polymeric moieties), but preferably it is alow molecular weight organic moiety with up to 100, or more preferablyup to 40 carbon atoms and, optionally, a molecular weight Mw of 1000 orless. It is preferred that the organic moiety is compatible with theactivation reaction described herein and does not adversely affect thedescribed reaction mechanism. Suitable groups and moieties are wellknown to those skilled in the art or can be readily identified byroutine experimentation.

In a preferred embodiment, the organic moiety can be a linear orbranched, substituted or unsubstituted alkyl with 1 to x carbon atoms;linear or branched, substituted or unsubstituted alkenyl with 2 to xcarbon atoms; linear or branched, substituted or unsubstituted alkinylwith 2 to x carbon atoms; linear or branched, substituted orunsubstituted alkoxy with 1 to x carbon atoms; substituted orunsubstituted cycloalkyl with 3 to x carbon atoms; substituted orunsubstituted cycloalkenyl with 3 to x carbon atoms; substituted orunsubstituted aryl with 6 to x carbon atoms; and substituted orunsubstituted heteroaryl with 3 to x carbon atoms; with x being anyinteger of 2 or more, preferably up to 50, more preferably up to 30.

In a further embodiment of the present invention, the organic moiety canbe a linear or branched, substituted or unsubstituted alkyl with 1 to 40carbon atoms; linear or branched, substituted or unsubstituted alkenylwith 3 to 40 carbon atoms; linear or branched, substituted orunsubstituted alkoxy with 1 to 40 carbon atoms, substituted orunsubstituted cycloalkyl with 5 to 40 carbon atoms; substituted orunsubstituted cycloalkenyl with 5 to 40 carbon atoms; substituted orunsubstituted aryl with 5 to 40 carbon atoms; and substituted orunsubstituted heteroaryl with 5 to 40 carbon atoms.

In another embodiment, the organic moiety can be a linear or branched,substituted or unsubstituted alkyl with 1 to 20 carbon atoms; linear orbranched, substituted or unsubstituted alkenyl with 3 to 20 carbonatoms; linear or branched, substituted or unsubstituted alkoxy with 1 to20 carbon atoms, substituted or unsubstituted cycloalkyl with 5 to 20carbon atoms; substituted or unsubstituted cycloalkenyl with 5 to 20carbon atoms; substituted or unsubstituted aryl with 5 to 14 carbonatoms; and substituted or unsubstituted heteroaryl with 5 to 14 carbonatoms.

The organic moiety can also be a combination of any of the above-definedgroups, including but not limited to alkylaryl, arylalkyl,alkylheteroaryl and the like, to name only a few, all of which may besubstituted or unsubstituted.

The term “substituted” as used herein in relation to the above moietiesrefers to a substituent other than hydrogen. Such a substitutent ispreferably selected from the group consisting of halogen, —OH, —OOH,—NH₂, —NO₂, —ONO₂, —CHO, —CN, —CNOH, —COOH, —SH, —OSH, —CSSH, —SCN,—SO₂OH, —CONH₂, —NH—NH₂, —NC, —CSH —OR, —NRR′, —C(O)R, —C(O)OR,—(CO)NRR′, —NR′C(O)R, —OC(O)R, aryl with 5 to 20 carbon atoms,cycloalk(en)yl with 3 to 20 carbon atoms, 3- to 8-memberedheterocycloalk(en)yl, and 5- to 20-membered heteroaryl, wherein R and R′are independently selected from hydrogen, alkyl with 1 to 10 carbonatoms, alkenyl with 2 to 10 carbon atoms, alkynyl with 2 to 10 carbonatoms, aryl with 5 to 14 carbon atoms, cycloalk(en)yl with 3 to 20carbon atoms, 5- to 14-membered heteroaryl, comprising 1 to 4heteroatoms selected from nitrogen, oxygen, and sulfur, and 5- to14-membered heterocycloalk(en)yl, comprising 1 to 4 heteroatoms selectedfrom nitrogen, oxygen, and sulfur. Any of these substituents may againbe substituted, it is however preferred that these substituents areunsubstituted.

Alkyl refers to a saturated hydrocarbon moiety, such as methyl, ethyl,and the like.

Alkenyl and Alkynyl comprise at least one carbon-carbon double bonds ortriple bonds, respectively, and are otherwise defined as alkyl above.

Cycloalkyl refers to a non-aromatic carbocyclic moiety, such ascyclopentanyl, cyclohexanyl, and the like.

Cycloalkenyl refers to non-aromatic carbocyclic compounds that compriseat least one C—C double bond.

Similarly, heterocycloalk(en)yl relates to cycloalk(en)yl groups wherein1 or more ring carbon atoms are replaced by heteroatoms, preferablyselected from nitrogen, oxygen, and sulfur.

Aryl relates to an aromatic ring that is preferably monocyclic orconsists of condensed aromatic rings. Preferred aryl substituents aremoieties with 6 to 14 carbon atoms, such as phenyl, naphthyl,anthracenyl, and phenanthrenyl.

Heteroaryl refers to aromatic moieties that correspond to the respectivearyl moiety wherein one or more ring carbon atoms have been replaced byheteroatoms, such as nitrogen, oxygen, and sulfur.

All of the afore-mentioned groups can be substituted or unsubstituted.When substituted the substituent can be selected from the above list ofsubstituents.

The term “at least one” as used herein relates to one or more, forexample 1, 2, 3, 4, 5, 6, 7, 8, 9 or more of the referenced species.

Halogen as used herein refers to F, Cl, Br, and I.

In various embodiments of the present invention, the compound of formula(I) is an α,β-saturated compound, i.e. there is a single bond connectingthe α- and β-carbon atom.

In various embodiments of the invention, moiety R₁ of Formula (I) and(II) is an alkyl with 1 to 5, preferably 3 carbon atoms.

In various other embodiments, moiety R₁ of Formula (I) and (II) is anaryl, selected from the group consisting of phenyl, furane, andnaphthalene, which optionally can be substituted, preferably by halogen,alkyl with 1 to 5 carbon atoms, and/or alkoxy with 1 to 5 carbon atoms.

In a further embodiment of the present invention, the compound ofFormula (II) is selected from the group consisting of 4-Nitrophenyl3-(para-tolyl)propanoate, 4-Nitrophenyl 3-(4-methoxyphenyl)propanoate,4-Nitrophenyl 3-(4-fluorophenyl)propanoate, 4-Nitrophenyl3-(4-chlorophenyl)propanoate, 4-Nitrophenyl 3-(4-bromophenyl)propanoate,4-Nitrophenyl 3-(naphthalen-1-yl)propanoate, 4-Nitrophenyl3-(furan-2-yl)propanoate, 4-Nitrophenyl hexanoate, 4-nitrophenyl3-(3-(cyclopentyloxy)-4-methoxyphenyl)propanoate, 4-nitrophenylbutyrate, 4-nitrophenyl propionate, and cinammaldehyde.

The term “electrophilic group” as used herein refers to a group thatresults from the reaction of an electrophile, as described below, withthe compound of Formula (IV).

In a preferred embodiment of the present invention, the moieties R₃ andR₄ of the compound of Formula (III) combine to form together with thecarbon atoms to which they are attached a substituted or unsubstituted5- to 40-membered cycloalkyl, cycloalkenyl, heteroalicyclic, aryl, orheteroaryl ring.

In various embodiments, the compound of Formula (III) is a compound ofFormula (V)

wherein R₅ is as defined above and R₆ is selected from the groupconsisting of hydrogen, halogen, —OH, —OOH, —NH₂, —NO₂, —ONO₂, —CHO,—CN, —CNOH, —COOH, —SH, —OSH, —CSSH, —SCN, —SO₂OH, —CONH₂, —NH—NH₂, —NC,—CSH, or any organic moiety.

R₆ can be selected from the group consisting of substituted orunsubstituted, linear or branched alkyl with 1-20 carbon atoms;substituted or unsubstituted, linear or branched alkenyl with 1-20carbon atoms; substituted or unsubstituted cycloalkyl with 5 to 20carbon atoms; substituted or unsubstituted cycloalkenyl with 5 to 20carbon atoms; substituted or unsubstituted aryl with 5-14 carbon atoms;and substituted or unsubstituted heteroaryl with 5-14 carbon atoms.Preferably, R₆ is selected from the group consisting of -iso-Pr,-tert-Bu, —CH₂Ph, —CH₂-iso-Pr, and —CH₂-tert-Bu. More preferably, R₆ isselected from the group consisting of —CH₂-tert-Bu and —CH₂-iso-Pr.

In one embodiment of the compound of Formula (V), R₅ is aryl. PreferablyR₅ is selected from the group consisting of phenyl and mesitylene, morepreferably R₅ is phenyl.

In a preferred embodiment, the compound of Formula (V) is selected fromthe group consisting of

In various embodiments, the compound of Formula (III) or (V) issynthesized from a compound of Formula (VI)

wherein X is any anion and R₃-R₅ are as defined above.

In various embodiments of the present invention, X can be selected fromthe group consisting of F⁻, Cl⁻, Br⁻, I⁻, OH⁻, HSO₃ ⁻, SO₃ ²⁻, SO₄ ²⁻,NO₂ ⁻, NO₃ ⁻, PO₄ ³⁻, BF₄ ⁻, PF₆ ⁻, ClO₄ ⁻, OTf⁻, acetate, citrate,formiate, glutarate, lactate, malate, malonate, oxalate, pyruvate, andtartrate. In a preferred embodiment of the present invention, X isselected from the group consisting of F⁻, Cl⁻, Br⁻, I⁻, BF₄ ⁻, OTf⁻, andacetate.

In another embodiment, the compound of Formula (VI) is a compound ofFormula (VII)

wherein R₅ and R₆ are as defined above.

In still another embodiment of the present invention, the compound ofFormula (VII) is selected from the group consisting of

In a preferred embodiment, the compound of Formula (III) or (V) isgenerated in situ from a compound of Formula (VI) or (VII).

The term “in situ” as used herein means in the reaction mixture.Specifically, this means that the respective compound is synthesized inthe reaction mixture.

The term “leaving group” as used herein refers to a moiety that isreleased from a molecule it was covalently bound to by keeping the pairof electrons previously forming the bond. A leaving group can be asingle atom, a molecule, or a functional group. These groups can be ananion or a neutral molecule. The leaving group may have a −I effect. Theleaving group of the present invention can be any leaving group which issuitable for the described reaction. In various embodiments, the leavinggroup can be selected from the group of hydrogen, halogen, −N₂ ⁺, —OR₂⁺, —OSO₂C₄F₉, —OSO₂CF₃, —OSO₂F, —OTs, —OMs, —OH₂ ⁺, —OHR⁺, —ONO₂,—OPO(OH)₂, —SR₂, —NR₃, —OCOR, —NH₃ ⁺, and —O—C₆H₄-para-NO₂, and R can beany organic residue or moiety. In a preferred embodiment, the leavinggroup is —O—C₆H₄-para-NO₂.

The reactions can be carried out in an organic solvent. The organicsolvent used in the present invention can be any organic solvent whichis suitable. In a preferred embodiment, the organic solvent is selectedfrom the group consisting of tert-Butanol, toluene, THF, CH₃CN, CH₂Cl₂,dioxane, ethyl acetate, and mixtures thereof. For the different steps of(i), i.e. activating a compound of Formula (I), and (ii), i.e. reactingthe compound of Formula (IV) with an electrophile, different or the sameorganic solvents can be used.

In various embodiments, both steps (i) and (ii) are conducted in aone-pot synthesis.

The term “one-pot synthesis” as used herein means that the reactions (i)and (ii) according to the present invention are carried out in the samereaction vessel without any purification step of an intermediate.

In various embodiments, the base in the reaction mixture is present inan amount of 100 to 300 mol-%, preferably 115 to 250 mol-%, morepreferably 130 to 200 mol-%, most preferably about 150 mol-%, based onthe total amount of the compound of Formula (I).

“About”, as used herein, refers to the numerical value it relates to±10%.

In various embodiments of the present invention, the electrophile can beany suitable electrophile. “Electrophile”, as used herein, generallyrelates to any reagent, such as atom or molecule, that is attracted toelectrons and participates in the chemical reaction by accepting anelectron pair in order to bind to the nucleophile. In variousembodiments, the electrophile may be a Lewis acid. In preferredembodiments, the electrophile is selected from the group consisting ofF₂, Cl₂, Br₂, I₂, alkyl-LG, alkenyl-LG, alkoxy-LG, acyl-LG, aryl-LG,heteroaryl-LG, hydrazone, and a carbonyl compound. “LG” is a leavinggroup and is defined as above. The electrophile can also be any Michaelacceptor.

In specific embodiments, the electrophile is selected from the group ofoptionally αβ-unsaturated, linear or branched, substituted orunsubstituted ketone; optionally α,β-unsaturated, linear or branched,substituted or unsubstituted aldehyde; optionally α,β-unsaturated,linear or branched, substituted or unsubstituted esters; optionallyα,β-unsaturated, linear or branched, substituted or unsubstitutedtrifluoroketone; optionally α,β-unsaturated, linear or branched,substituted or unsubstituted carboxamide; optionally α,β-unsaturated,linear or branched, substituted or unsubstituted amide; optionallyα,β-unsaturated, linear or branched, substituted or unsubstitutednitrile; optionally linear or branched, substituted or unsubstitutedimine; linear or branched, substituted or unsubstituted nitrone; linearor branched, substituted or unsubstituted diazene, and optionallyα,β-unsaturated, linear or branched, substituted or unsubstitutedhydrazone. More preferably, the electrophile is selected from the groupconsisting of α,β-unsaturated, linear or branched, substituted orunsubstituted ketone, trifluoroketone, and hydrazone.

In various embodiments, the base used in accordance with the presentinvention contains one or more nitrogen atom(s). The base used can beany suitable base and may, for example, be selected from the groupconsisting of pyrrolidine; N(CH₃)₃; N(CH₂CH₃)₃; (iso-Propyl)₂NH;2,2,6,6-Tetramethyl-1-piperidin; LDA (Lithium diisopropylamid); LHMDS(Lithium bis(trimethylsilyl)amide); LTMP (Lithiumtetramethylpiperidide); and 4-aminopyridine.

In a preferred embodiment, the base is an amidine. The amidine can beselected from the group consisting of DBU(1,8-Diazabicyclo[5.4.0]undec-7-en); DBN(1,5-Diazobicyclo[3.4.0]non-5-ene); and DABCO(1,4-Diazobicyclo[2.2.2]octan).

In another embodiment of the present invention, the base is aphosphazine. The phosphazine can be selected from the group consistingof P₁-tert-Bu-tris(tetramethylene);2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine;and 1-Ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ⁵,4λ⁵-catenadi(phosphazene).

In various embodiments, the reaction temperature used in steps (i) and(ii) of the method disclosed herein ranges from 0° C. to 85° C. Thereaction temperature of these steps can also be from 15° C. to 55° C.Preferably, the reaction temperature used in steps (i) and (ii) is about20 to 30° C., more preferably about 25° C.

The reaction temperatures of steps (i) and (ii) may be selectedindependently from each other, for instance the reaction temperature ofstep (i) may be 25° C. whereas the reaction temperature of step (ii) maybe 40° C.

In various embodiments of the invention, the reaction time is from 0.1hours to 72 hours. The reaction time can also be from 1 hour to 48hours. In still another embodiment, the reaction time is from 5 hours to36 hours, preferably about 24 hours.

In various embodiments of the present invention, a molecular sieve ispresent in the reaction mixture, preferably with apertures of a size ofapproximately 4 Å.

The method disclosed herein may comprise additional reaction steps whichmay be carried out after or between the reaction steps (i) and (ii)according to the present invention. Such additional steps may includesteps for catalyst regeneration, Michael reactions, aldol reactions,lactonization, and/or decarboxylation.

The present invention also encompasses a compound of Formula (VI) or(VII).

In various embodiments, the compound of Formula (VI) or (VII) may beselected from the group consisting of

wherein X is defined as above.

Also encompassed by the present invention is the use of a compound ofFormula (VI) or (VII) for activating a compound of Formula (II), whereinsaid compounds are as defined above.

In various embodiments, for this use the compound of Formula (VI) or(VII) is selected from the group consisting of

wherein X is defined as above.

By “comprising”, as used herein, is meant including, but not limited to,whatever follows the word “comprising”. Thus, use of the term“comprising” indicates that the listed elements are required ormandatory, but that other elements are optional and may or may not bepresent.

The following examples are provided to better illustrate the claimedinvention and are not be interpreted in any way as limiting the scope ofthe invention. All specific compounds, materials, and methods describedbelow, in whole or in part, fall within the scope of the invention.These specific compounds, materials, and methods are not intended tolimit the invention, but merely to illustrate specific embodimentsfalling within the scope of the invention. One skilled in the art maydevelop equivalent compounds, materials, and use without the exercise ofinventive capacity and without departing from the scope of theinvention. It is the intention of the inventors that such variations areincluded in the scope of the present invention.

All references cited herein are incorporated by reference in theirentirety.

EXAMPLES

General Information

Commercially available materials purchased from Alfa Aesar orSigma-Aldrich were used as received. HPLC grade CH₃CN (purchased fromTEDIA) was dried over 4 Å molecular sieve prior use. Toluene and DCM wasdried over Pure Solv solvent purification system. THF was distilled oversodium. Other solvents were dried over 4 Å molecular sieve prior use.Proton nuclear magnetic resonance (¹H-NMR) spectra were recorded on aBruker (400 MHz) spectrometer. Chemical shifts were recorded in partsper million (ppm, δ) relative to tetramethylsilane (δ=0.00) orchloroform (δ=7.26, singlet). ¹H NMR splitting patterns are designatedas singlet (s), doublet (d), triplet (t), quartet (q), dd (doublet ofdoublets); m (multiplets), and etc. All first-order splitting patternswere assigned on the basis of the appearance of the multiplet. Splittingpatterns that could not be easily interpreted are designated asmultiplet (m) or broad (br). Carbon nuclear magnetic resonance (¹³C-NMR)spectra were recorded on a Bruker (400 MHz) (100 MHz) spectrometer. Highresolution mass spectral analysis (HRMS) was performed on Finnigan MAT95 XP mass spectrometer (Thermo Electron Corporation). The determinationof enantiomeric excess was performed via chiral HPLC analysis usingShimadzu LC-20AD HPLC workstation. X-ray crystallography analysis wasperformed on Bruker X8 APEX X-ray diffractionmeter. Optical rotationswere measured using a 1 mL cell with a 1 dm path length on a JascoP-1030 polarimeter and are reported as follows: [α]^(rt) _(D) (c is ingm per 100 mL solvent). Analytical thin-layer chromatography (TLC) wascarried out on Merck 60 F254 pre-coated silica gel plate (0.2 mmthickness). Visualization was performed using a UV lamp or potassiumpermanganate stain.

Substrate Preparation

The synthesis of 4-nitrophenyl esters (1b-i) was performed by adoptingknown procedures.^([1])

4-Nitrophenyl 3-(para-tolyl)propanoate: White solid; 69% yield; ¹H NMR(400 MHz, CDCl₃) δ=2.34 (s, 3H), 2.91 (t, J=7.6 Hz, 2H), 3.04 (t, J=7.6Hz, 2H), 7.12-7.25 (m, 6H), 8.22-8.26 (m, 2H); ¹³C NMR (100 MHz, CDCl₃)δ=170.5, 155.4, 145.3, 136.6, 136.2, 129.4, 128.3, 125.2, 122.5, 36.1,30.4, 21.1; HRMS(ESI) calcd for C₁₆H₁₆NO₄ (M+H)⁺: 286.1079, Found:286.1088.

4-Nitrophenyl 3-(4-methoxyphenyl)propanoate: White solid; 88% yield; ¹HNMR (400 MHz, CDCl₃) δ=2.90 (t, J=7.2 Hz, 2H), 3.02 (t, J=7.2 Hz, 2H),3.80 (s, 3H), 6.87 (d, J=8.8 Hz, 2H), 7.18-7.26 (m, 4H), 8.24 (d, J=8.8Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ=170.5, 158.4, 155.4, 145.3, 131.7,129.4, 125.2, 122.5, 114.1, 55.3, 36.2, 30.0; HRMS(ESI) calcd forC₁₆H₁₆NO₅ (M+H)⁺: 302.1028, Found: 302.1032.

4-Nitrophenyl 3-(4-fluorophenyl)propanoate: White solid; 87% yield; ¹HNMR (400 MHz, CDCl₃) δ=2.89-2.93 (m, 2H), 3.06 (t, J=7.2 Hz, 2H),6.99-7.04 (m, 2H), 7.17-7.24 (m, 4H), 8.23-8.27 (m, 2H); ¹³C NMR (100MHz, CDCl₃) δ=170.3, 162.9, 160.5, 155.3, 145.4, 135.4, 135.3, 129.9,129.8, 125.2, 122.4, 115.6, 115.4, 36.0, 30.0; HRMS(ESI) calcd forC₁₅H₁₃FNO₄ (M+H)⁺: 290.0829, Found: 290.0841.

4-Nitrophenyl 3-(4-chlorophenyl)propanoate: White solid; 90% yield; ¹HNMR (400 MHz, CDCl₃) δ=2.90-2.94 (m, 2H), 3.05 (t, J=7.2 Hz, 2H),7.18-7.31 (m, 6H), 8.25 (d, J=9.2 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃)δ=170.2, 155.3, 145.4, 138.1, 132.5, 129.8, 128.8, 125.2, 122.4, 35.7,30.1; HRMS(ESI) calcd for C₁₅H₁₃ClNO₄ (M+H)⁺: 306.0533, Found: 306.0542.

4-Nitrophenyl 3-(4-bromophenyl)propanoate: White solid; 83% yield; ¹HNMR (400 MHz, CDCl₃) δ=2.90-2.94 (m, 2H), 3.03 (t, J=7.2 Hz, 2H),7.13-7.22 (m, 4H), 7.45 (d, J=7.2 Hz, 2H), 8.23-8.26 (m, 2H); ¹³C NMR(100 MHz, CDCl₃) δ=170.2, 155.3, 145.4, 138.7, 131.8, 130.2, 125.2,122.4, 120.5, 35.7, 30.1; HRMS(ESI) calcd for C₁₅H₁₃BrNO₄Na (M+Na)⁺:371.9847, Found: 371.9846.

4-Nitrophenyl 3-(naphthalen-1-yl)propanoate: White solid; 83% yield; ¹HNMR (400 MHz, CDCl₃) δ=3.06 (t, J=7.6 Hz, 2H), 3.54 (t, J=7.6 Hz, 2H),7.15-7.19 (m, 2H), 7.40-7.58 (m, 4H), 7.77 (dd, J=7.2, 2.4 Hz, 1H),7.88-7.90 (m, 1H), 8.05 (d, J=8.4 Hz, 1H), 8.20-8.24 (m, 2H); ¹³C NMR(100 MHz, CDCl₃) δ=170.6, 155.4, 145.4, 135.7, 134.0, 131.6, 129.1,127.6, 126.4, 126.3, 125.8, 125.6, 125.2, 123.2, 122.4, 35.3, 28.0;HRMS(ESI) calcd for C₁₉H₁₆NO₄ (M+H)⁺: 322.1079, Found: 322.1093.

4-Nitrophenyl 3-(furan-2-yl)propanoate: White solid; 80% yield; ¹H NMR(400 MHz, CDCl₃) δ=2.94-2.97 (m, 2H), 3.11 (t, J=7.2 Hz, 2H), 6.10 (dd,J=3.2, 0.4 Hz, 1H), 6.32 (dd, J=3.2, 1.6 Hz, 1H), 7.23-7.27 (m, 2H),7.35 (d, J=1.2 Hz, 1H), 8.24-8.28 (m, 2H); ¹³C NMR (100 MHz, CDCl₃)δ=170.1, 155.4, 153.3, 145.4, 141.6, 125.2, 122.4, 110.4, 105.9, 33.0,23.4; HRMS(ESI) calcd for C₁₃H₁₂NO₅ (M+H)⁺: 262.0715, Found: 262.0710.

4-Nitrophenyl hexanoate: colorless liquid; 95% yield; ¹H NMR (400 MHz,CDCl₃) δ=0.94 (t, J=7.2 Hz, 3H), 1.36-1.43 (m, 4H), 1.76 (q, J=7.6 Hz,2H), 2.60 (t, J=7.2 Hz, 2H), 7.27-7.29 (m, 2H), 7.26 (d, J=8.8 Hz, 2H);¹³C NMR (100 MHz, CDCl₃) δ=171.3, 155.6, 145.3, 125.2, 122.4, 34.3,31.2, 24.4, 22.3, 13.9; HRMS(ESI) calcd for C₁₂H₁₆NO₄ (M+H)⁺: 238.1079,Found: 238.1079.

4-nitrophenyl 3-(3-(cyclopentyloxy)-4-methoxyphenyl)propanoate: yellowoil; 90% yield; ¹H NMR (400 MHz, CDCl₃) δ=1.55-1.62 (m, 2H), 1.84-1.91(m, 6H), 2.90 (t, J=7.2 Hz, 2H), 3.01 (t, J=7.2 Hz, 2H), 3.84 (s, 3H),4.73-4.76 (m, 1H), 6.76-6.84 (m, 3H), 7.19 (d, J=8.8 Hz, 2H), 8.25 (d,J=8.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ=170.5, 155.4, 148.9, 147.8,145.3, 132.1, 125.2, 122.4, 120.3, 115.6, 112.2, 80.5, 56.2, 36.2, 32.8,30.4, 24.0; HRMS(ESI) calcd for C₂₁H₂₄NO₆ (M+H)⁺: 386.1604, Found:386.1603.

Catalytic Preparation

The triazolium-based compound of Formulae (III) and (V) (A-H) wereprepared by adopting known procedures.^([2)]

Example 1:(R)-5-Isopropyl-2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-iumtetrafluoroborate: White solid; [α]_(D) ²³ (c 2.0, CH₃CN)=+49.6°; ¹H NMR(400 MHz, CDCl₃) δ 0.91 (d, J=6.8 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H),2.42-2.59 (m, 2H), 2.88-2.98 (m, 1H), 3.09-3.18 (m, 1H), 3.22-3.30 (m,1H), 4.89-4.94 (m, 1H), 7.48-7.54 (m, 3H), 7.86 (d, J=6.8 Hz, 2H), 10.09(s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 162.2, 136.9, 135.6, 130.7, 130.1,120.8, 66.2, 31.1, 28.4, 21.7, 18.4, 16.2; HRMS(ESI) calcd forC₁₄H₁₈N₃(M)⁺: 228.1501, Found: 228.1496.

Example 2:(R)-5-(Tert-butyl)-2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-iumtetrafluoroborate: White solid; [α]_(D) ²³ (c 2.0, CH₃CN)=+45.4°; ¹H NMR(400 MHz, CDCl₃) δ 1.04 (s, 9H), 2.58-2.65 (m, 1H), 2.94-3.22 (m, 3H),4.75-4.77 (m, 1H), 7.49-7.55 (m, 3H), 7.88 (d, J=7.2 Hz, 2H), 10.01 (s,1H); ¹³C NMR (100 MHz, CDCl₃) δ 162.7, 137.5, 135.5, 130.7, 130.1,121.0, 70.5, 34.6, 29.0, 25.6, 21.7; HRMS(ESI) calcd for C₁₅H₂₀N₃(M)⁺:242.1657, Found: 242.1655.

Example 3:(R)-5-Isobutyl-2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-iumtetrafluoroborate: White solid; [α]_(D) ²³ (c 2.0, CH₃CN)=+40.7°; ¹H NMR(400 MHz, CDCl₃) δ 0.97-1.00 (m, 6H), 1.59-1.75 (m, 2H), 2.14-2.20 (m,1H), 2.42-2.47 (m, 1H), 3.02-3.07 (m, 1H), 3.19-3.29 (m, 2H), 4.99-5.03(m, 1H), 7.47-7.52 (m, 3H), 7.81-7.84 (m, 2H), 10.05 (s, 1H); ¹³C NMR(100 MHz, CDCl₃) δ 161.7, 136.6, 135.6, 130.6, 130.1, 120.8, 60.2, 42.9,33.3, 25.2, 22.9, 21.6, 21.3; HRMS(ESI) calcd for C₁₅H₂₀N₃(M)⁺:242.1657, Found: 242.1657.

Example 4:(R)-5-Neopentyl-2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-iumtetrafluoroborate: White solid; [α]_(D) ²³ (c 2.0, CH₃CN)=+48.2°; ¹H NMR(400 MHz, CDCl₃) δ 0.99 (s, 9H), 1.67 (dd, J=13.6, 11.2 Hz, 1H), 2.36(dd, J=12.8, 2.0 Hz, 1H), 2.45-2.51 (m, 1H), 3.08-3.22 (m, 2H),3.27-3.36 (m, 1H), 4.98-5.01 (m, 1H), 7.45-7.51 (m, 3H), 7.81-7.83 (m,2H), 10.03 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 161.4, 136.5, 135.6,130.5, 130.1, 120.8, 59.8, 48.2, 35.8, 30.4, 29.7, 22.1; HRMS(ESI) calcdfor C₁₆H₂₂N₃(M)⁺: 256.1814, Found: 256.1812.

General Procedure of the Catalytic Reactions

Example 5: Reaction of esters and enones to synthesize 3 (3a as anexample): A dry 10 mL Schlenk tube equipped with a magnetic stirring barwas successively charged with ester 1a (109 mg, 0.40 mmol), chalcone 2a(42 mg, 0.20 mmol), NHC pre-catalyst H (13.8 mg, 0.04 mmol) and 4 ÅMolecular Sieve (200 mg). The tube was closed with a septum, evacuated,and refilled with nitrogen. To this mixture was added dry CH₃CN (0.5mL), followed by the addition of DBU (46 μL, 0.30 mmol) via a microsyringe. After stirred for 24 hours at room temperature, the reactionmixture was analyzed by ¹H NMR analysis (to determine d.r.), and thendirectly applied to silica gel column chromatography (1% v/v ethylacetate in hexane) to afford 3a as a colorless oil in 66% yield, 7:1d.r. and 95:5 e.r.

Example 6: The synthesis γ-lactone 5a from ester 1a and trifluoroketone4a was performed using a procedure similar to that used in the catalyticsynthesis of 3a: A dry 10 mL Schlenk tube equipped with a magneticstirring bar was successively charged with ester 1a (109 mg, 0.40 mmol),2,2,2-trifluoro-1-phenylethanone 4a (28 μL, 0.20 mmol), NHC pre-catalystH (13.8 mg, 0.04 mmol) and 4 Å Molecular Sieve (200 mg). The tube wasclosed with a septum, evacuated, and refilled with nitrogen. To thismixture was added dry toluene (1.0 mL), followed by the addition of DBU(46 μL, 0.30 mmol) via a micro syringe. After stirred for 48 hours at 0°C., the reaction mixture was concentrated under reduced pressure. Thecrude residue was analyzed by ¹H NMR analysis (to determine d.r.), andthen directly applied to silica gel column chromatography (2:1 v/vhexanes/dichloromethane) to afford γ-lactone products-a mixture ofdiastereomers (5a, and 5a′) as a colorless oil in 54% yield with 1.3:1d.r., 91:9 and 94:6 e.r. for the major and minor diastereomerrespectively. For the trans- and cis-isomers, (4S, 5S)-5a and (4S,5R)-5a′ were obtained as the major enantiomers respectively. Therelative and absolute chemistry were determined by comparing the chiralphase HPLC trace with authentic samples prepared using literaturemethods.^([3]) HPLC (Chiralcel OD, 99:1 hexanes/i-PrOH, 0.7 mL/min),t_(r) (5a-major)=22.6 min, t_(r) (5a-minor)=42.3 min, t_(r)(5a′-major)=20.0 min, t_(r) (5a′-minor)=68.7 min.

TABLE S1 Organocatalytic approach to activate saturated ester β-carbonas nucleophile for asymmetric reaction.

Compound of 3a 3a 3a Entry Formula (VI) 3a:4a yield d.r. e.r. 1 A n.d.<5 n.d — 2 B >20:1 85 14:1 — 3 C    5:1 79  7:1 — 4 D >20:1 69 11:1  87:13 5 E >20:1 30  8:1   95:5 6 F    8:1 54 16:1   87:13 7 G >20:1 7112:1   91:9 8* G >20:1 74 14:1   91:9 9* H >20:1 70(66)  7:1 95.5:4.5Unpurified reaction mixture. The enantiomeric ratio (e.r.) of 3a (majordiastereomer) was determined via chiral phase HPLC analysis, absoluteconfiguration of 3a was determined via X-ray structure of 3y. Structureof a-activation product 4a was confirmed via ¹H NMR analysis. *Reactionsrun with 150 mol. % DBU, yield for 3a in parentheses (entry 9) wasisolated yield. NHC, N-heterocyclic carbene. DBU,1,8-diazabicyclo[5.4.0]undec-7-ene. MS, molecular sieve. Mes,1,3,5-trimethylbenzene. i-Pr, iso-propyl. t-Bu, tert-butyl.

TABLE S2 Condition optimization for synthesis of γ-lactone 5a and 5a′from ester 1a and triflouroketone 4a

Yield (5a + 5a′) d.r. Entry Solvent Temperature Time (h) (%)^([a])(5a:5a′)^([b]) e.r.^([c]) 1 CH₂Cl₂ RT 24 61 2.1:1 77:23/79:22 2 TolueneRT 24 56 1.3:1 89:11/92:8  3 CH₃CN RT 24 58 1.8:1 75:25/79:22 4 EthylAcetate RT 24 58 1.4:1 86:14/91:9  5 THF RT 24 57 1.3:1 86:14/91:9  6t-BuOH RT 24 73 3.0:1 72:28/75:25 7 Dioxane RT 24 49 1.4:1 87:13/90:10 8Toluene. 0° C. 24 45 1.3:1 91:9/94:6 9 Toluene. 0° C. 48 54 1.3:191:9/94:6 ^([a])Isolated yield. ^([b])Diastereomeric ratio, estimatedvia ¹H NMR analysis of crude reaction mixture. ^([c])Enatiomeric ratioof 5a and 5a′ respectively, estimated via chiral phase HPLC analysis.RT, room temperature, which is 25° C.

Example 7: The synthesis of γ-lactam 7a and 7a′ from ester 1a andhydrazone 6a was performed using a similar procedure to that for thepreparation of 5a above: A dry 10 mL Schlenk tube equipped with amagnetic stir bar was successively charged with ester 1a (55 mg, 0.2mmol), hydrazone 6a (22 mg, 0.10 mmol), NHC pre-catalyst H (6.9 mg, 0.02mmol) and 4 Å Molecular Sieve (200 mg). The tube was closed with aseptum, evacuated, and refilled with nitrogen. To this mixture was addeddry EA (0.5 mL), followed by the addition of DBU (23 μL, 0.15 mmol) viaa micro syringe. After being stirred for 48 hours at 40° C., thereaction mixture was concentrated under reduced pressure. The cruderesidue was analyzed by ¹H NMR analysis (to determine d.r.), and thenwas diluted with CH₂Cl₂ (15 mL) and washed with a 1:1 mixture ofsaturated aqueous NH₄Cl and water (10 mL). The aqueous layer wasextracted with CH₂Cl₂ (2×15 mL) and the combined organic layers weredried over anhydrous sodium sulfate, filtered, and concentrated. Theoily residue was applied to silica gel column chromatography (3:1 v/vhexanes/ethyl acetate) to afford γ-lactam products-a mixture ofdiastereomers as a colorless oil in 74% yield with 6:1 d.r., 97:3/90:10e.r. for the major and minor diastereomers respectively. The twodiastereomers could also be separated for HPLC, NMR, and opticalrotation analysis. The relative stereo-configurations of bothdiastereomers were determined by comparison with literaturesamples,^([4]) and the absolute configuration of the trans-isomer (7a)was determined via x-ray structure analysis. HPLC [Chiralcel IA, 75:20:5hexanes/(hexanes:i-PrOH:CH₃OH=75:20:5)/i-PrOH, 0.7 mL/min], t_(r)(7a-major)=88.3 min, t_(r) (7a-minor)=110.2 min, t_(r) (major enantiomerof the minor diastereomer)=66.7 min, t_(r) (minor enantiomer of theminor diastereomer)=72.9 min. Optical rotation: 7a, [α]_(D) ²³ (c 0.94,CH₂Cl₂)=−39.1°.

TABLE S3 Condition optimization for synthesis of γ-lactam 7a from ester1a and hydrazone 6a

Entry^([a]) Solvent Yield (%)^([b]) d.r.^([c]) e.r.^([d]) 1 CH₃CN 263.3:1 98:2/91:9 2 Toluene 72 5.8:1  97:3/89:11 3 Dioxane 95 3.6:1 97:3/90:10 4 Ethyl Acetate 82(74)^([e]) 6.0:1  97:3/90:10 5 THF 785.3:1 97:3/92:8 6 CH₂Cl₂ 71 4.0:1 97:3/92:8 7 t-BuOH 74 2.4:1 96:4/89:11 8^([f]) Ethyl Acetate 79 6.0:1  97:3/90:10 ^([a])Reactionwas carried out at 0.2M concentration of 6a, with the presence of 200 mg4Å Molecular Sieve. ^([b])Yields were estimated via ¹H NMR yield.^([c])Diastereomeric ratio, estimated via ¹H NMR analysis of crudereaction mixture. ^([d])Enantiomeric ratio of the 7a and and itsdiastereomer respectively, estimated via chiral phase HPLC analysis.^([e])Isolated yield. ^([f])20 mmol % Mg(Ot-Bu)₂. Note: Thecorresponding racemic products (for the above three type of reactions)for chiral phase HPLC method development were prepared using similarprocedrues in presence of achiral catalyst B or C.

Example 8: Stereochemistry determination (3y & 7j) via X-raycrystillographic analysis. Good quality crystal of 3y (colorless flakycrystal) was obtained by vaporization of a hexane solution of compound3y. CCDC 900975 contains the supplementary crystallographic data thatcan be obtained free of charge from The Cambridge Crystallographic DataCentre via www.ccdc.cam.ac.uk/data request/cif.

Product 7j was crystallized as a colorless crystal via vaporization of ahexane/ethyl acetate solution, and its absolute configuration wasdetermined by x-ray structure analaysis. CCDC 910100 contains thesupplementary crystallographic data that can be obtained free of chargefrom The Cambridge Crystallographic Data Centre viawww.ccdc.cam.ac.uk/data request/cif.

Synthetic Utilities: Transformation of Catalytic Reaction Products toBioactive Compounds

Example 9: Synthesis of (S)-baclefon 9c: A dry 10 mL Schlenk tubeequipped with a magnetic stir bar was successively charged with γ-lactam7c (5:1 d.r., 97:3 e.r., 0.2 mmol). The tube was closed with a septum,evacuated, and refilled with nitrogen. To this mixture was added a 0.1 Msolution of Sml₂ (5.2 equiv) in THF at 0° C., followed by the additionof EtOH (0.5 mL) via a syringe. After stirring for 1.5 hours at 0° C.,the reaction mixture was concentrated under reduced pressure. The cruderesidue was diluted with ethyl acetate (15 mL) and washed with water.The aqueous layer was extracted with ethyl acetate (2×15 mL) and thecombined organic layers were dried over anhydrous sodium sulfate,filtered, and concentrated. The oily residue was applied to silica gelcolumn chromatography (1:100 v/v methanol/DCM) to afford trans γ-lactam8c as a colorless oil in 72% isolated yield, 96:4 e.r., and cis γ-lactamwith 13% isolated yield. Compound 8c can be converted to (S)-Baclofen 9cby adopting a literature procedure.^([5])

Example 10: Synthesis of (S)-rolipram 9i: Compound 7i-2 was preparedusing a procedure similar to that for the synthesis of 8c above.Compound 7i-2 (50 mg, 0.14 mmol) was dissolved in 5 mL THF and LiBH₄ (8mg, 0.36 mmol) was added in portions. After stirring at room temperaturefor 4 h, the reaction was quenched with 2 N HCl in an ice bath. Themixture was extracted with ethyl acetate, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. Purification bysilicon gel column chromatography gave the product 7i-3 as colorless oil(43 mg, 98% yield).

Compound 7i-3 (30.5 mg, 0.1 mmol) was dissolved in 3 mL anhydrousCH₂Cl₂, and TBSCI (16.5 mg, 0.11 mmol) and DMAP (14.4 mg, 0.12 mmol) wasadded. After stirring at room temperature for 3 h, the reaction wasquenched with 1N HCl The mixture was extracted with ethyl acetate, driedover anhydrous Na₂SO₄, and concentrated under reduced pressure. Theresidue was dissolved in 3 mL anhydrous CH₂Cl₂, and Boc₂O (24.0 mg, 0.11mmol) and DMAP (14.4 mg, 0.12 mmol) was added. After stirring at roomtemperature overnight, the reaction was quenched with 1N HCl, extractedwith ethyl acetate, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The crude residue was dissolved in 3 mL anhydrous THFand AcOH (6 μL, 0.1 mmol). TBAF (1 M in THF, 0.2 mL, 0.2 mmol) wasadded. The reaction was stirred at room temperature and monitored by TLCfor completion. The mixture was extracted with ethyl acetate, washedwith brine and dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. Purification by column chromatography on silicon gelgave the product 8i as colorless oil (27 mg, 67% yield, 96:4 e.r.).

Compound 8i can be converted to (S)-Rolipram 9i according to literatureprocedure.^([6])

Comparison of Our Ester Reactions with α,β-Unsaturated Aldehyde (Enal)Reactions

NHC-catalyzed reactions of ester 1a (OR ENAL 10a) with chalcone 2a(Table S4): The four enantiomers (from two diastereomers) of product 3aand their ratios were assigned via chiral phase HPLC analsyis. The RISratios of each chiral center were then calculated. The resultssummerized in Table S3 showed that reactions with enone 2a of from ester1a or the corresponding enal 10a gave very different results. Severalobservations are given below:

TABLE S4 Comparison of enal reactions and our ester β-activationreactions (chalcone as electrophile)

Entry Conditions Reaction 3a Carbon #1 (R/S) Carbon #2 (R/S) 1 20 mol %H, ester (1a) 66% yield, 7:1 d.r. 87:13 94:6 150 mol % DBU, CH₃CN 96:4e.r.(trans-3a) (as Table 1, entry 9) 81:19 e.r. (cis-3a) 2 as entry 1above enal (10a) 51% yield, 1.8:1 d.r. 44:56 66:34 57:43 e.r.(trans-3a)88:12 e.r. (cis-3a) 3 as entry 2 above enal (10a) 43% yield, 1.2:1 d.r.41:59 68:32 except with 2.3 eq DBU 57:43 e.r.(trans-3a) and 2.0 eq 4-90:10 e.r. (cis-3a) NO₂PHOH 4 as entry 1 above ester (1a) 25% yield,16:1 d.r. 84:16 81:19 except NHC = I 85:15 e.r.(trans-3a) 26:74 e.r.(cis-3a) 5 as entry 4 above enal (10a) 24% yield, 1.8:1 d.r. 28:72 52:4836:64 e.r.(trans-3a) 92:8e.r. (cis-3a)(a) A comparison of entry 1 and 2 showed that the ester reaction gavemuch better d.r. and e.r. More remarkably, the enal reaction gave 3awith a much lower and even opposite e.r. For example, for carbon #1 ofproduct 3a, the ester reaction (entry 1) favored R-configuration (87:13R/S), while the enal reaction (entry 2) favored S-configuration (44:56R/S).(b) Since the ester reaction (entry 1) released 4-NO2-PhOH in thecatalytic reaction; we wondered if the difference in e.r. and d.r wascaused by the phenol side product. We therefore added 2.0 equivalents of4-NO2-PhOH as an additive to the enal reaction (entry 3). To maintain abasic medium for effective reaction, 2.3 eq DBU was also added. Acomparison of entry 3 and 2 showed that the additive had only verylittle influence on the stereo-selectivities. The R/S ratios for eachchiral carbon center remained nearly the same (e.g., for carbon #1,44:56 R/S in entry 2, as compared to 41:59 R/S in entry 3 when phenoladditive was introduced)(c) A comparison of entries 1-3 suggested that that the “similar”homoenolate intermediates obtained using the enal and our esterapproaches showed different reactivities and selectivities. Morespecifically, the enal homoenolate intermediate comes from addition ofNHC to the aldehyde group of enal to form a Breslow intermediate. Incontrast, our ester “homoenolate” is obtained through β-carbondeprotonation of an “enolate intermediate”. The ester “homoenolate”intermediate with a formal nucleophilic β-carbon may be stabilized in adifferent form. Additional mechanistic studies are in progress.(d) Similar differences between ester and enal reactions were observedusing other conditions and NHC catalysts. For example, with I as an NHCpre-catalyst, the ester and enal reactions gave oppositeenantioselectivities for both trans- and cis-3a and both carbon chiralcenters of 3a (entries 4-5). Notably, as observed by Bodepreviously,^([7]) the enal reaction gave cis-cyclopetene product withhigh e.r., (e.g., 92:8 e.r., for cis-3a, entry 5), but trans-isomer withlow e.r. (e.g., 36:64 e.r. for trans-3a, entry 5). These results againclearly demonstrate the practical utilities of our ester activationstrategy in enantioselective synthesis.Similar Results Were Also Observed When Hydrazone (Table S5) orTrifluoroketone (Table S6) Were Used the Electrophiles:

TABLE S5 Comparison of enal reactions and our ester β-activationreactions (hydrazone as electrophile)

Entry Conditions Reaction 7a Carbon #1 (R/S) Carbon #2 (R/S) 1 20 mol %H, ester (1a) 74% yield, 6:1 d.r. 150 mol % DBU, EA(0.2 M), 97:3e.r.(trans-7a) 13:87 97:3 40° C., 48 h 90:10 e.r. (cis-7a) 2 as entry 1above enal (10a) 20% yield, 1:2.2 d.r. 40:60 e.r.(trans-7a) 10:90  7:933:97 e.r. (cis-7a) 3 as entry 2 above enal (10a) 20% yield, 1:1.4 d.r.except with 2.3 eq DBU 84:16 e.r.(trans-7a) 13:87 49:51 and 2.0 eq4-NO₂PHOH 11:89 e.r. (cis-7a) 4 as entry 1 above ester (1a) 44% yield,3.8:1 d.r. except NHC = I 77:23 e.r.(trans-7a) 30:70 77:23 76:24 e.r.(cis-7a) 5 as entry 4 above enal (10a) 5% yield, nd d.r. 28:72 17:8335:65 e.r.(trans-7a) 10:90 e.r. (cis-7a)

TABLE S6 Comparison of enal reactions and our ester β-activationreactions (trifluoroketone as electrophile)

Entry Conditions Reaction 5a + 5a′ Carbon #1 Carbon #2 (R/S) (R/S) 1 20mol % H, ester (1a) 54% yield, 1.3:1 d.r. 150 mol % DBU, 91:9 e.r.(5a) 8:92 46:54 Tol. (0.2 M), 0° C., 48 h 94:6 e.r. (5a′) 2 as entry 1 aboveenal (10a) 38% yield, 1.4:1 d.r. 59:41 e.r.(5a) 34:66 54:46 80:20 e.r.(5a′) 3 as entry 2 above enal (10a) 62% yield, 1:1.1 d.r. except with2.3 eq DBU 61:39 e.r.(5a) 36:64 53:47 and 2.0 eq 4-NO₂PHOH 64:36 e.r.(5a′) 4 as entry 1 above ester (1a) 17% yield, 1.2:1 d.r. except NHC = I65:35 e.r.(5a) 38:62 49:51 59:41 e.r. (5a′) 5 as entry 4 above enal(10a) 19% yield, 1.5:1 d.r. 45:55 44:56 59:41 e.r.(5a) 49:51 e.r. (5a′)Characterizations of Products

¹H NMR and ¹³C NMR characterization of exemplary compounds is providedin the following.

Example 11: (1R,2R)-Cyclopent-3-ene-1,2,4-triyltribenzene: [α]_(D) ²³ (c2.23, CH₂Cl₂)=−138.9°; 95:5 e.r. as determined by HPLC (Chiralcel OD,99.8:0.2 hexanes/i-PrOH, 0.3 mL/min), t_(r) (major)=35.8 min, t_(r)(minor)=46.9 min.

Example 12: ((1R,5R)-5-(p-Tolyl)cyclopent-3-ene-1,3-diyl)dibenzene:[α]_(D) ²³ (c 1.85, CH₂Cl₂)=−133.8°; 97:3 e.r. as determined by HPLC(Chiralcel ADH, 99.9:0.1 hexanes/i-PrOH, 0.3 mL/min), t_(r) (major)=39.1min, t_(r) (minor)=51.4 min.

Example 13:((1R,5R)-5-(4-Methoxyphenyl)cyclopent-3-ene-1,3-diyl)dibenzene: [α]_(D)²³ (c 2.83, CH₂Cl₂)=−116.5°; 95:5 e.r. as determined by HPLC (ChiralcelIA, 99.8:0.2 hexanes/i-PrOH, 0.3 mL/min), t_(r) (major)=45.4 min, t_(r)(minor)=41.7 min.

Example 14:((1R,5R)-5-(4-Fluorophenyl)cyclopent-3-ene-1,3-diyl)dibenzene: [α]_(D)²³ (c 1.95, CH₂Cl₂)=−110.4°; 96:4 e.r. as determined by HPLC (ChiralcelIA, 99.8:0.2 hexanes/i-PrOH, 0.3 mL/min), t_(r) (major)=29.1 min, t_(r)(minor)=23.4 min.

Example 15:((1R,5R)-5-(4-Chlorophenyl)cyclopent-3-ene-1,3-diyl)dibenzene: [α]_(D)²³ (c 2.47, CH₂Cl₂)=−117.7°; 95:5 e.r. as determined by HPLC (ChiralcelIA, 99.8:0.2 hexanes/i-PrOH, 0.3 mL/min), t_(r) (major)=32.0 min, t_(r)(minor)=25.8 min.

Example 16:((1R,5R)-5-(4-Bromophenyl)cyclopent-3-ene-1,3-diyl)dibenzene: [α]_(D) ²³(c 2.46, CH₂Cl₂)=−127.0°; 95:5 e.r. as determined by HPLC (ChiralcelODH, 99.8:0.2 hexanes/i-PrOH, 0.3 mL/min), t_(r) (major)=65.2 min, t_(r)(minor)=97.6 min.

Example 17: 1-((1R,5R)-3,5-Diphenylcyclopent-2-en-1-yl)naphthalene:colorless gum; [α]_(D) ²³ (c 1.17, CH₂Cl₂)=+22.3°; ¹H NMR (400 MHz,CDCl₃) δ=2.98-3.03 (m, 1H), 3.40-3.46 (m, 1H), 3.53-3.57 (m, 1H), 4.89(dd, J=4.4, 2.0 Hz, 1H), 6.42 (dd, J=4.0, 1.6 Hz, 1H), 6.71-6.75 (m,1H), 7.23-7.45 (m, 11H), 7.59-7.61 (m, 2H), 7.64-7.79 (m, 2H), 7.85 (d,J=8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ=147.0, 142.9, 136.0, 134.1,131.8, 128.7, 128.6, 128.5, 128.5, 128.1, 127.6, 127.1, 127.0, 126.4,125.9, 125.8, 125.7, 125.6, 125.5, 124.2, 124.0, 56.6, 52.8, 42.0;HRMS(ESI) calcd for C₂₇H₂₃ (M+H)⁺: 347.1800, Found: 347.1797; 95:5 e.r.as determined by HPLC (Chiralcel ODH, 99.8:0.2 hexanes/i-PrOH, 0.3mL/min), t_(r) (major)=28.7 min, t_(r) (minor)=27.4 min.

Example 18: 2-((1R,5R)-3,5-Diphenylcyclopent-2-en-1-yl)furan: [α]_(D) ²³(c 2.54, CH₂Cl₂)=−78.7°; 91:9 e.r. as determined by HPLC (Chiralcel IA,99.8:0.2 hexanes/i-PrOH, 0.3 mL/min), t_(r) (major)=28.0 min, t_(r)(minor)=21.2 min.

Example 19: ((1R,5R)-5-Propylcyclopent-3-ene-1,3-diyl)dibenzene:[αa]_(D) ²³ (c 0.62, CH₂Cl₂)=−24.0°; 91:9 e.r. as determined by HPLC(Chiralcel IA, 99.8:0.2 hexanes/i-PrOH, 0.3 mL/min), t_(r) (major)=16.0min, t_(r) (minor)=13.7 min.

Example 20: ((1R,5R)-5-Methylcyclopent-3-ene-1,3-diyl)dibenzene:colorless gum; [α]_(D) ²³ (c 0.63, CH₂Cl₂)=+48.2°; ¹H NMR (400 MHz,CDCl₃) δ=1.17 (d, J=6.4 Hz, 3H), 2.86-2.93 (m, 1H), 2.98-3.07 (m, 2H),3.17-3.24 (m, 1H), 6.11-6.12 (m, 1H), 7.20-7.34 (m, 8H), 7.45-7.47 (m,2H); ¹³C NMR (100 MHz, CDCl₃) δ=145.8, 140.0, 136.4, 130.8, 128.4,128.3, 127.5, 127.1, 126.1, 125.6, 53.3, 49.4, 42.2, 19.9; HRMS(ESI)calcd for C₁₈H₁₉ (M+H)⁺: 235.1487, Found: 235.1500; 94:6 e.r. asdetermined by HPLC (Chiralcel IA, 99.9:0.1 hexanes/i-PrOH, 0.3 mL/min),t_(r) (major)=15.9 min, t_(r) (minor)=14.0 min.

Example 21: Cyclopent-3-ene-1,3-diyldibenzene: colorless gum; ¹H NMR(400 MHz, CDCl₃) δ=2.64-2.69 (m, 1H), 2.83-2.88 (m, 1H), 2.99-3.01 (m,1H), 3.18 (ddd, J=9.2, 2.4, 1.2 Hz, 1H), 3.62-3.67 (m, 1H), 6.22 (dd,J=4.0, 2.0 Hz, 1H), 7.18-7.34 (m, 8H), 7.47 (dd, J=4.0, 1.2 Hz, 2H); ¹³CNMR (100 MHz, CDCl₃) b=147.2, 141.5, 136.4, 128.5, 128.4, 127.1, 127.0,126.0, 125.6, 124.8, 43.5, 42.0, 41.8; HRMS(ESI) calcd for C₁₇H₁₇(M+H)⁺: 221.1330, Found: 221.1342.

Example 22: ((3R,4R)-4-(p-Tolyl)cyclopent-1-ene-1,3-diyl)dibenzene:colorless gum; [α]_(D) ²³ (c 1.13, CH₂Cl₂)=−147.4°; ¹H NMR (400 MHz,CDCl₃) δ=2.33 (s, 3H), 2.96-3.02 (m, 1H), 3.29-3.44 (m, 2H), 4.09-4.12(m, 1H), 6.25 (dd, J=3.6, 2.0 Hz, 1H), 7.09-7.38 (m, 12H), 7.52-7.54 (m,2H); ¹³C NMR (100 MHz, CDCl₃) δ=145.0, 142.4, 142.2, 136.1, 135.8,129.2, 128.5, 128.4, 128.2, 127.5, 127.4, 127.2, 126.4, 125.8, 60.8,54.2, 42.1, 21.1; HRMS(ESI) calcd for C₂₄H₂₃ (M+H)⁺: 311.1800, Found:311.1798; 95:5 e.r. as determined by HPLC (Chiralcel OD, 99.8:0.2hexanes/i-PrOH, 0.3 mL/min), t_(r) (major)=29.9 min, t_(r) (minor)=37.9min.

Example 23:((3R,4R)-4-(4-Chlorophenyl)cyclopent-1-ene-1,3-diyl)dibenzene: colorlessgum; [α]_(D) ²³ (c 1.27, CH₂Cl₂)=−116.3°; ¹H NMR (400 MHz, CDCl₃)δ=2.93-2.99 (m, 1H), 3.29-3.42 (m, 2H), 4.05-4.07 (m, 1H), 6.24 (dd,J=3.6, 2.0 Hz, 1H), 7.11-7.39 (m, 12H), 7.51-7.54 (m, 2H); ¹³C NMR (100MHz, CDCl₃) δ=144.5, 143.8, 142.1, 135.8, 132.0, 128.7, 128.6, 128.6,128.5, 128.0, 127.7, 127.4, 126.6, 125.8, 60.9, 54.0, 41.9; HRMS(ESI)calcd for C₂₃H₁₉Cl (M+Na)⁺: 353.1073, Found: 353.1060; 95:5 e.r. asdetermined by HPLC (Chiralcel IA, 99.8:0.2 hexanes/i-PrOH, 0.3 mL/min),t_(r) (major)=31.8 min, t_(r) (minor)=25.1 min.

Example 24:((3R,4R)-4-(4-Bromophenyl)cyclopent-1-ene-1,3-diyl)dibenzene: colorlessgum; [α]_(D) ²³ (c 2.42, CH₂Cl₂)=−117.1°; ¹H NMR (400 MHz, CDCl₃) δ=2.96(dd, J=15.2, 7.2 Hz, 1H), 3.32-3.41 (m, 2H), 4.05-4.07 (m, 1H), 6.24(dd, J=3.6, 2.0 Hz, 1H), 7.10-7.42 (m, 12H), 7.52-7.54 (m, 2H); ¹³C NMR(100 MHz, CDCl₃) δ=144.5, 144.4, 142.1, 135.8, 131.6, 129.1, 128.6,128.5, 128.0, 127.7, 127.4, 126.6, 125.8, 120.0, 60.9, 54.1, 41.8;HRMS(ESI) calcd for C₂₃H₂₀Br (M+H)⁺: 375.0748, Found: 375.0728; 95:5e.r. as determined by HPLC (Chiralcel IA, 99.9:0.1 hexanes/i-PrOH, 0.3mL/min), t_(r) (major)=37.4 min, t_(r) (minor)=27.6 min.

Example 25:((3R,4R)-4-(4-Nitrophenyl)cyclopent-1-ene-1,3-diyl)dibenzene: colorlessgum; [α]_(D) ²³ (c 1.61, CH₂Cl₂)=−104.4°; ¹H NMR (400 MHz, CDCl₃) δ=3.02(dd, J=16.0, 7.2 Hz, 1H), 3.37-3.44 (m, 1H), 3.53-3.57 (m, 1H),4.10-4.12 (m, 1H), 6.27 (dd, J=3.6, 2.0 Hz, 1H), 7.11-7.13 (m, 2H),7.24-7.42 (m, 8H), 7.53-7.55 (m, 2H), 8.13-8.17 (m, 2H); ¹³C NMR (100MHz, CDCl₃) δ=153.2, 146.7, 144.0, 142.1, 135.5, 128.7, 128.6, 128.2,127.9, 127.8, 127.4, 126.9, 125.9, 123.9, 70.0, 54.4, 41.7; HRMS(ESI)calcd for C₂₃H₂₀NO₂ (M+H)⁺: 342.1494, Found: 342.1500; 95:5 e.r. asdetermined by HPLC (Chiralcel IA, 99:1 hexanes/i-PrOH, 0.3 mL/min),t_(r) (major)=86.5 min, t_(r) (minor)=46.4 min.

Example 26:((3R,4R)-4-(3-Nitrophenyl)cyclopent-1-ene-1,3-diyl)dibenzene: colorlessgum; [α]_(D) ²³ (c 1.03, CH₂Cl₂)=−53.4°; ¹H NMR (400 MHz, CDCl₃)δ=2.98-3.04 (m, 1H), 3.37-3.43 (m, 1H), 3.53-3.59 (m, 1H), 4.11-4.14 (m,1H), 6.26 (d, J=1.2 Hz, 1H), 7.12-7.45 (m, 9H), 7.53 (d, J=7.6 Hz, 3H),8.06-8.09 (m, 1H), 8.14 (d, J=2.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃)δ=148.5, 147.4, 144.0, 142.0, 135.5, 133.8, 129.5, 128.8, 128.7, 128.6,127.9, 127.4, 126.9, 125.9, 122.2, 121.6, 60.8, 54.2, 41.8; HRMS(ESI)calcd for C₂₃H₁₉NO₂Na (M+Na)⁺: 364.1313, Found: 364.1298; 96:4 e.r. asdetermined by HPLC (Chiralcel ADH, 99:1 hexanes/i-PrOH, 0.3 mL/min),t_(r) (major)=72.1 min, t_(r) (minor)=48.4 min.

Example 27:((3R,4R)-4-(2-Nitrophenyl)cyclopent-1-ene-1,3-diyl)dibenzene: colorlessgum; [α]_(D) ²³ (c 1.0, CH₂Cl₂)=−55.0°; ¹H NMR (400 MHz, CDCl₃)δ=2.89-2.95 (m, 1H), 3.50-3.56 (m, 1H), 3.89-3.95 (m, 1H), 4.22 (dd,J=5.6, 2.4 Hz, 1H), 6.30 (d, J=2.0 Hz, 1H), 7.11-7.39 (m, 9H), 7.52-7.57(m, 3H), 7.65-7.69 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ=150.1, 143.8,142.1, 140.1, 135.5, 132.8, 128.7, 128.6, 128.5, 128.0, 127.9, 127.3,127.1, 126.9, 125.9, 123.8, 60.4, 47.7, 42.4; HRMS(ESI) calcd forC₂₃H₁₉NO₂Na (M+Na)⁺: 364.1313, Found: 364.1318; 96:4 e.r. as determinedby HPLC (Chiralcel IA, 99.9:0.1 hexanes/i-PrOH, 0.3 mL/min), t_(r)(major)=63.8 min, t_(r) (minor)=56.3 min.

Example 28: 2-((1R,2R)-2,4-Diphenylcyclopent-3-en-1-yl)thiophene:[α]_(D) ²³ (c 2.56, CH₂Cl₂)=−70.8°; 94:6 e.r. as determined by HPLC(Chiralcel IA, 99.8:0.2 hexanes/i-PrOH, 0.3 mL/min), t_(r) (major)=29.0min, t_(r) (minor)=25.5 min.

Example 29: 2-((3R,4R)-3,4-Diphenylcyclopent-1-en-1-yl)furan: [α]_(D) ²³(c 1.66, CH₂Cl₂)=−127.4°; 94:6 e.r. as determined by HPLC (Chiralcel OD,99.8:0.2 hexanes/i-PrOH, 0.3 mL/min), t_(r) (major)=34.4 min, t_(r)(minor)=49.9 min.

Example 30: ((1R,2R)-4-(p-Tolyl)cyclopent-3-ene-1,2-diyl)dibenzene:colorless gum; [α]_(D) ²³ (c 1.00, CH₂Cl₂)=−112.4°; ¹H NMR (400 MHz,CDCl₃) δ=2.37 (s, 3H), 2.96-3.02 (m, 1H), 3.29-3.46 (m, 2H), 4.10-4.13(m, 1H), 6.20 (t, J=1.6 Hz, 1H), 7.13-7.31 (m, 12H), 7.42-7.49 (m, 2H);¹³C NMR (100 MHz, CDCl₃) δ=145.6, 145.1, 142.1, 137.4, 133.2, 129.2,128.5, 128.4, 127.5, 127.3, 127.1, 126.4, 126.3, 125.7, 60.8, 54.5,42.0, 21.3; HRMS(ESI) calcd for C₂₄1-H₂₃ (M+H)⁺: 311.1800, Found:311.1804; 95:5 e.r. as determined by HPLC (Chiralcel IA, 99.8:0.2hexanes/i-PrOH, 0.3 mL/min), t_(r) (major)=26.1 min, t_(r) (minor)=24.2min.

Example 31:((1R,2R)-4-(4-Chlorophenyl)cyclopent-3-ene-1,2-diyl)dibenzene: colorlessgum; [α]_(D) ²³ (c 2.14, CH₂Cl₂)=−89.5°; ¹H NMR (400 MHz, CDCl₃)δ=2.94-3.01 (m, 1H), 3.26-3.34 (m, 1H), 3.42-3.48 (m, 1H), 4.11-4.14 (m,1H), 6.24 (dd, J=3.6, 2.0 Hz, 1H), 7.12-7.34 (m, 12H), 7.43-7.46 (m,2H); ¹³C NMR (100 MHz, CDCl₃) δ=145.1, 144.6, 141.1, 134.5, 133.2,128.9, 128.6, 128.5, 128.5, 127.4, 127.3, 127.1, 126.5, 126.4, 60.8,54.5, 42.0; HRMS(ESI) calcd for C₂₃H₂₀Cl (M+H)⁺: 331.1254, Found:331.1277; 95:5 e.r. as determined by HPLC (Chiralcel IA, 99.8:0.2hexanes/i-PrOH, 0.3 mL/min), t_(r) (major)=31.4 min, t_(r) (minor)=29.3min.

Example 32:((1R,2R)-4-(4-Bromophenyl)cyclopent-3-ene-1,2-diyl)dibenzene: [α]_(D) ²³(c 2.78, CH₂Cl₂)=−87.5°; 96:4 e.r. (1R, 2R)-isomer as determined by HPLC(Chiralcel IA, 99.9:0.1 hexanes/i-PrOH, 0.3 mL/min), t_(r) (major)=35.2min, t_(r) (minor)=32.4 min.

Example 33:4,4′-((1R,5R)-5-Phenylcyclopent-3-ene-1,3-diyl)bis(chlorobenzene):[α]_(D) ²³ (c 2.5, CH₂Cl₂)=−94.4°; 95:5 e.r. isomer as determined byHPLC (Chiralcel IA, 99.8:0.2 hexanes/i-PrOH, 0.3 mL/min), t_(r)(major)=49.5 min, t_(r) (minor)=38.1 min.

Example 34:4,4′-((1R,5R)-5-Phenylcyclopent-3-ene-1,3-diyl)bis(bromobenzene):colorless gum; [α]_(D) ²³ (c 3.45, CH₂Cl₂)=−68.8°; ¹H NMR (400 MHz,CDCl₃) δ=2.89-2.96 (m, 1H), 3.25-3.27 (m, 1H), 3.30-3.43 (m, 1H),4.03-4.05 (m, 1H), 6.23 (d, J=1.6 Hz, 1H), 7.08-7.49 (m, 13H); ¹³C NMR(100 MHz, CDCl₃) δ=144.2, 144.0, 141.1, 134.7, 131.7, 131.6, 130.7,129.1, 128.9, 128.6, 127.4, 126.7, 121.5, 120.1, 60.9, 54.1, 41.8;HRMS(ESI) calcd for C₂₃H₁₉Br₂ (M+H)⁺: 452.9854, Found: 452.9868; 95:5e.r. as determined by HPLC (Chiralcel IA, 99.8:0.2 hexanes/i-PrOH, 0.3mL/min), t_(r) (major)=59.2 min, t_(r) (minor)=46.3 min.

Example 35:1-((1R,2R)-4-(4-Chlorophenyl)-2-(4-methoxyphenyl)cyclopent-3-en-1-yl)naphthalene:[α]_(D) ²³ (c 3.0, CH₂Cl₂)=−124.4°; 97:3 e.r. as determined by HPLC(Chiralcel OD, 98:2 hexanes/i-PrOH, 0.3 mL/min), t_(r) (major)=59.8 min,t_(r) (minor)=38.4 min.

Note: For the products characterized as below, the two diastereomers(e.g., 5a and 5a′) were isolated as a mixture.

Example 36: 4,5-Diphenyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one: 91:9e.r. (5a), 94:6 e.r. (5a′) as determined by HPLC (Chiralcel OD, 99:1hexanes/i-PrOH, 0.7 mL/min), t_(r) (5a-major)=23.1 min, t_(r)(5a-minor)=44.0 min, t_(r) (5a′-major)=19.8 min, t_(r) (5a′-minor)=71.3min.

Example 37:4-phenyl-5-(p-tolyl)-5-(trifluoromethyl)dihydrofuran-2(3H)-one: 93:7e.r. (5b), 95:5 e.r. (5b′) as determined by HPLC (Chiralcel OD, 99.8:0.2hexanes/i-PrOH, 0.7 mL/min), t_(r) (5b-major)=30.5 min, t_(r)(5b-minor)=81.3 min, t_(r) (5b′-major)=34.5 min, t_(r) (5b′-minor)=106.5min.

Example 38:5-(4-chlorophenyl)-4-phenyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one:94:6 e.r. (5c), 94:6 e.r. (5c′) as determined by HPLC (Chiralcel IA,99:1 hexanes/i-PrOH, 0.7 mL/min), t_(r) (5c-major)=18.2 min, t_(r)(5c-minor)=38.5 min, t_(r) (5c′-major)=19.4 min, t_(r) (5c′-minor)=69.2min.

Example 39:5-(4-bromophenyl)-4-phenyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one:colorless oil; ¹H NMR (400 MHz, CDCl₃) δ=2.74-2.81 (trans, m, 1H),2.95-2.97 (cis, m, 1H), 3.17-3.32 (cis, m, 1H), 3.34-3.39 (trans, m,1H), 3.93 (cis, t, J=9.6 Hz, 1H), 4.26 (trans, dd, J=9.6, 5.2 Hz, 1H),6.84-6.87 (trans, m, 2H), 7.01 (trans, d, J=8.4 Hz, 2H), 7.13-7.16(trans, m, 3H), 7.27-7.33 (trans+cis, m, 4H), 7.39-7.42 (cis, m, 5H),7.56-7.58 (cis, m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ=173.4 (trans), 172.7(cis), 137.4 (trans), 134.5, 133.2, 132.0, 131.1, 130.5, 129.3, 129.0,128.9, 128.9, 128.8, 128.7, 128.3, 128.1, 127.3, 127.3, 125.7, 124.1,123.4, 122.9, 88.2 (q, J=290 Hz) (trans), 87.3 (q, J=260 Hz) (cis), 51.6(cis), 45.7 (trans), 36.8 (trans), 35.1 (cis); HRMS (ESI) calcd forC₁₇H₁₃O₂F₃Br (M+H)⁺: 385.0051, Found: 385.0055; 93:7 e.r. (5d), 94:6e.r. (5d′) as determined by HPLC (Chiralcel IB, 98:2 hexanes/i-PrOH, 0.5mL/min), t_(r) (5d-major)=22.1 min, t_(r) (5d-minor)=44.7 min, t_(r)(5d′-major)=24.3 min, t_(r) (5d′-minor)=74.6 min.

Example 40:4-phenyl-5-(thiophen-2-yl)-5-(trifluoromethyl)dihydrofuran-2(3H)-one:90:10 e.r. (5e), 91:9 e.r. (5e′) as determined by HPLC (Chiralcel OD,99:1 hexanes/i-PrOH, 0.7 mL/min), t_(r) (5e-major)=41.6 min, t_(r)(5e-minor)=70.5 min, t_(r) (5e′-major)=26.6 min, t_(r) (5e′-minor)=87.1min.

Example 41:5-phenyl-4-(p-tolyl)-5-(trifluoromethyl)dihydrofuran-2(3H)-one:colorless oil; ¹H NMR (400 MHz, CDCl₃) δ=2.21 (trans, s, 3H), 2.39 (cis,s, 3H), 2.71-2.77 (trans, m, 1H), 2.90 (cis, q, J=8.8 Hz, 1H), 3.14(cis, dd, J=18.0, 10.0 Hz, 1H), 3.26-3.33 (trans, m, 1H), 3.97 (cis, t,J=5.2 Hz, 1H), 4.25 (trans, dd, J=9.2, 5.6 Hz, 1H), 6.71 (trans, d,J=8.0 Hz, 2H), 6.91 (trans, d, J=8.0 Hz, 2H), 7.12-7.22 (trans+cis, m,10H), 7.44 (trans, dd, J=6.4, 3.6 Hz, 2H), 7.53-7.54 (cis, m, 2H); ¹³CNMR (100 MHz, CDCl₃) δ=173.9 (trans), 173.4 (cis), 138.6 (cis), 137.6(trans), 135.6 (cis), 134.4 (trans), 131.3 (trans), 130.7 (cis), 129.5,129.4, 129.2, 128.8, 128.7, 128.3, 127.8, 127.0, 126.9, 126.0, 125.6,125.3, 123.2, 122.5, 88.5 (q, J=280 Hz) (trans), 87.4 (q, J=280 Hz)(cis), 51.2 (cis), 45.5 (trans), 36.8 (trans), 35.3 (cis), 21.1 (cis),21.0 (trans); HRMS(ESI) calcd for C₁₈H₁₆O₂F₃ (M+H)⁺: 321.1102, Found:321.1101; 92:8 e.r. (5f), 95:5 e.r. (5f) as determined by HPLC(Chiralcel OD, 95:5 hexanes/i-PrOH, 0.7 mL/min), t_(r) (5f-major)=19.5min, t_(r) (5f-minor)=34.7 min, t_(r) (5f′-major)=14.8 min, t_(r)(5f′-minor)=40.3 min.

Example 42:4-(4-fluorophenyl)-5-phenyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one:colorless oil; ¹H NMR (400 MHz, CDCl₃) δ=2.70-2.76 (m, 1H), 3.29-3.37(m, 1H), 4.28 (dd, J=9.6, 5.6 Hz, 1H), 4.03-4.05 (m, 1H), 6.80 (d, J=6.8Hz, 4H), 7.11-7.22 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ=173.5, 163.3,160.8, 133.4, 133.3, 131.1, 130.1, 130.0, 129.0, 128.0, 126.8, 115.6,115.4, 88.4 (q, J=290 Hz), 45.2, 36.8; HRMS(ESI) calcd for C₁₇H₁₃O₂F₄(M+H)⁺: 325.0852, Found: 325.0852; 95:5 e.r. (5g), 92:8 e.r. (5g′) asdetermined by HPLC (Chiralcel OD, 99:1 hexanes/i-PrOH, 0.7 mL/min),t_(r) (5g-major)=28.5 min, t_(r) (5g-minor)=26.1 min, t_(r)(5g′-major)=23.1 min, t_(r) (5g′-minor)=39.8 min.

Example 43:4-(4-bromophenyl)-5-phenyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one:colorless oil; ¹H NMR (400 MHz, CDCl₃) δ=2.67-2.74 (trans, m, 1H),2.93-2.96 (cis, m, 1H), 3.06-3.09 (cis, m, 1H), 3.29-3.67 (trans, m,1H), 3.97 (cis, t, J=9.2 Hz, 1H), 4.25 (trans, dd, J=9.6, 5.2 Hz, 1H),6.71 (trans, d, J=8.8 Hz, 2H), 7.12-7.26 (trans+cis, m, 10H), 7.44-7.46(trans, m, 2H), 7.50-7.56 (cis, m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ=173.3(trans), 172.8 (cis), 136.7 (trans), 135.2 (cis), 133.0, 132.0, 131.7,131.0, 130.9, 130.0, 129.7, 129.2, 128.9, 128.1, 126.8, 126.8, 125.9,125.5, 123.0, 122.9, 121.9, 88.9 (q, J=280 Hz) (trans), 87.6 (q, J=280Hz) (cis), 51.0 (cis), 45.4 (trans), 36.7 (trans), 35.1 (cis); HRMS(ESI)calcd for C₁₇H₁₂O₂F₃BrNa (M+Na)⁺: 406.9870, Found: 406.9860; 94:6 e.r.(5h), 96:4 e.r. (5h′) as determined by HPLC (Chiralcel OD, 99:1hexanes/i-PrOH, 0.7 mL/min), t_(r) (5h-major)=52.9 min, t_(r)(5h-minor)=114.9 min, t_(r) (5h′-major)=41.4 min, t_(r)(5h′-minor)=130.2 min.

Example 44:4-(furan-2-yl)-5-phenyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one: 84:16e.r. (5i), 84:16 e.r. (5i′) as determined by HPLC (Chiralcel OJ-H, 95:5hexanes/i-PrOH, 0.5 mL/min), t_(r) (5i-major)=18.9 min, t_(r)(5i-minor)=28.9 min, t_(r) (5i′-major)=74.1 min, t_(r) (5i′-minor)=62.6min.

Example 45: (2R,3R)-ethyl1-benzamido-5-oxo-3-phenylpyrrolidine-2-carboxylate: colorless oil;[α]_(D) ²³ (c 0.94, CH₂Cl₂)=−39.1°. ¹H NMR (400 MHz, CDCl₃) δ 0.81 (t,J=7.2 Hz, 3H), 2.92 (d, J=8.8 Hz, 2H), 3.64-3.72 (m, 1H), 3.77-3.85 (m,1H), 4.10-4.17 (m, 1H), 4.96 (d, J=8.8 Hz, 1H), 7.25-7.36 (m, 5H), 7.45(t, J=8.0 Hz, 2H), 7.56 (t, J=7.6 Hz, 1H), 7.83 (d, J=8.0 Hz, 2H), 8.29(s, 1H). HRMS(ESI) calcd for C₂₀H₂₀N₂O₄ (M+H)⁺: 353.1501, Found:353.1496; 97:3 e.r. as determined by HPLC [Chiralcel IA, 75:20:5hexanes/(hexanes:i-PrOH:CH₃OH=90:5:5)/i-PrOH, 0.7 mL/min)], t_(r)(major)=110.2 min, t_(r) (minor)=88.3 min.

Example 46:(2R,3S)-ethyl1-benzamido-3-(4-fluorophenyl)-5-oxopyrrolidine-2-carboxylate:yellow oil; [α]_(D) ²³ (c 1.95, CH₂Cl₂)=−44.9°; ¹H NMR (400 MHz, CDCl₃)δ=1.23 (t, J=7.2 Hz, 3H), 2.63 (dd, J=17.6 Hz, 9.6 Hz, 1H), 3.04 (dd,J=17.6 Hz, 9.6 Hz, 1H), 3.56-3.61 (m, 1H), 4.17-4.29 (m, 2H), 4.68 (d,J=5.2 Hz, 1H), 7.09 (t, J=8.4 Hz, 2H), 7.41-7.49 (m, 4H), 7.55 (t, J=7.2Hz, 1H), 7.85 (d, J=7.2 Hz, 2H), 8.61 (bs, 1H); ¹³C NMR (100 MHz, CDCl₃)δ=172.5, 170.8, 166.1, 163.5, 161.0, 137.3 (d, J=3.0 Hz), 132.7, 131.2,128.9 (d, J=9.0 Hz), 128.7, 127.5, 116.0 (d, J=21.0 Hz), 67.3, 62.0,39.9, 36.8, 14.1; HRMS(ESI) calcd for C₂₀H₂₀N₂O₄F (M+H)⁺: 371.1407,Found: 371.1410; 97:3 e.r. as determined by HPLC [Chiralcel IA, 75:20:5hexanes/(hexanes:i-PrOH:CH₃OH=90:5:5)/i-PrOH, 0.7 mL/min)], t_(r)(major)=127.3 min, t_(r) (minor)=105.4 min.

Example 47:(2R,3S)-ethyl1-benzamido-3-(4-chlorophenyl)-5-oxopyrrolidine-2-carboxylate:yellow oil; [α]_(D) ²³ (c 1.89, CH₂Cl₂)=−67.2°; ¹H NMR (400 MHz, CDCl₃)δ=1.23 (t, J=7.2 Hz, 3H), 2.64 (dd, J=17.6 Hz, 6.4 Hz, 1H), 3.06 (dd,J=17.6 Hz, 9.6 Hz, 1H), 3.56-3.61 (m, 1H), 4.15-4.30 (m, 2H), 4.67 (d,J=5.6 Hz, 1H), 7.37-7.45 (m, 6H), 7.52 (t, J=7.6 Hz, 1H), 7.84 (d, J=7.2Hz, 2H), 8.83 (bs, 1H); ¹³C NMR (100 MHz, CDCl₃) δ=172.7, 170.7, 166.1,140.0, 133.6, 132.6, 131.1, 129.3, 128.7, 128.6, 127.6, 67.1, 62.0,40.0, 36.7, 14.1; HRMS(ESI) calcd for C₂₀H₂₀N₂O₄Cl (M+H)⁺: 387.1112,Found: 387.1112; 97:3 e.r. as determined by HPLC [Chiralcel IA, 75:20:5hexanes/(hexanes:i-PrOH:CH₃OH=90:5:5)/i-PrOH, 0.7 mL/min)], t_(r)(major)=136.0 min, t_(r) (minor)=112.0 min.

Example 48:(2R,3S)-ethyl1-benzamido-3-(4-bromophenyl)-5-oxopyrrolidine-2-carboxylate:yellow oil; [α]_(D) ²³ (c 2.49, CH₂Cl₂)=−61.8°; ¹H NMR (400 MHz, CDCl₃)δ=1.21 (t, J=7.2 Hz, 3H), 2.64 (dd, J=17.6 Hz, 6.4 Hz, 1H), 3.11 (dd,J=17.6 Hz, 9.6 Hz, 1H), 3.56-3.61 (m, 1H), 4.15-4.26 (m, 2H), 4.68 (d,J=5.6 Hz, 1H), 7.34-7.54 (m, 7H), 7.84 (d, J=7.2 Hz, 2H), 9.49 (bs, 1H);¹³C NMR (100 MHz, CDCl₃) δ=173.4, 170.7, 166.0, 140.4, 132.5, 132.2,130.9, 129.0, 128.6, 127.6, 121.7, 67.1, 62.0, 40.1, 36.8, 14.1;HRMS(ESI) calcd for C₂₀H₂₀N₂O₄Br⁺: 431.0606, Found: 431.0606; 97:3 e.r.as determined by HPLC [Chiralcel IA, 75:20:5hexanes/(hexanes:i-PrOH:CH₃OH=90:5:5)/i-PrOH, 0.7 mL/min)], t_(r)(major)=142.7 min, t_(r) (minor)=118.4 min.

Example 49: (2R,3S)-ethyl1-benzamido-5-oxo-3-(p-tolyl)pyrrolidine-2-carboxylate: yellow oil;[α]_(D) ²³ (c 2.41, CH₂Cl₂)=−46.8°; ¹H NMR (400 MHz, CDCl₃) δ=1.22 (t,J=7.2 Hz, 3H), 2.36 (s, 3H), 2.65 (dd, J=17.6 Hz, 9.6 Hz, 1H), 3.02 (dd,J=17.6 Hz, 9.6 Hz, 1H), 3.53-3.59 (m, 1H), 4.15-4.28 (m, 2H), 4.70 (d,J=6.0 Hz, 1H), 7.20 (d, J=7.6 Hz, 2H), 7.35-7.44 (m, 4H), 7.53 (t, J=7.2Hz, 1H), 7.85 (d, J=7.2 Hz, 2H), 8.67 (bs, 1H); ¹³C NMR (100 MHz, CDCl₃)δ=172.9, 171.0, 166.0, 138.3, 137.4, 132.5, 131.3, 129.8, 128.7, 127.6,127.1, 67.4, 61.9, 40.3, 36.8, 21.1, 14.1; HRMS(ESI) calcd forC₂₁H₂₃N₂O₄ (M+H)⁺: 367.1658, Found: 367.1657; 97:3 e.r. as determined byHPLC [Chiralcel IA, 75:20:5hexanes/(hexanes:i-PrOH:CH₃OH=90:5:5)/i-PrOH, 0.7 mL/min)], t_(r)(major)=108.1 min, t_(r) (minor)=86.0 min.

Example 50:(2R,3S)-ethyl1-benzamido-3-(4-methoxyphenyl)-5-oxopyrrolidine-2-carboxylate:yellow oil; [α]_(D) ²³ (c 2.2, CH₂Cl₂)=−69.9°; ¹H NMR (400 MHz, CDCl₃)δ=1.23 (t, J=7.2 Hz, 3H), 2.65 (dd, J=18.0 Hz, 6.8 Hz, 1H), 2.99 (dd,J=17.6 Hz, 9.6 Hz, 1H), 3.51-3.57 (m, 1H), 3.82 (s, 3H), 4.16-4.29 (m,2H), 4.68 (d, J=5.6 Hz, 1H), 6.93 (d, J=8.8 Hz, 2H), 7.39-7.47 (m, 4H),7.55 (t, J=7.2 Hz, 1H), 7.85 (d, J=7.2 Hz, 2H), 8.42 (bs, 1H); ¹³C NMR(100 MHz, CDCl₃) δ=172.6, 171.0, 166.0, 159.1, 133.5, 132.6, 131.4,128.8, 128.2, 127.5, 114.5, 67.5, 61.9, 55.3, 39.9, 36.8, 21.8, 14.2;HRMS(ESI) calcd for C₂₁H₂₃N₂O₅ (M+H)⁺: 383.1607, Found: 383.1608; 97:3e.r. as determined by HPLC [Chiralcel IA, 70:20:10hexanes/(hexanes:i-PrOH:CH₃OH=90:5:5)/i-PrOH, 0.7 mL/min)], t_(r)(major)=82.2 min, t_(r) (minor)=73.0 min.

Example 51:(2R,3S)-ethyl1-benzamido-3-(naphthalen-1-yl)-5-oxopyrrolidine-2-carboxylate:yellow oil; [α]_(D) ²³ (c 2.08, CH₂Cl₂)=−11.1°; ¹H NMR (400 MHz, CDCl₃)δ=1.15 (t, J=7.2 Hz, 3H), 2.79 (dd, J=17.2 Hz, 5.6 Hz, 1H), 3.21 (dd,J=17.6 Hz, 5.6 Hz, 1H), 4.16-4.26 (m, 2H), 4.43-4.48 (m, 1H), 5.02 (d,J=4.8 Hz, 1H), 7.44 (t, J=7.6 Hz, 2H), 7.52-7.61 (m, 4H), 7.83-7.94 (m,5H), 8.11 (d, J=8.4 Hz, 1H), 8.70 (bs, 1H); ¹³C NMR (100 MHz, CDCl₃)δ=172.8, 171.3, 166.2, 136.8, 134.1, 132.6, 131.4, 130.9, 129.3, 128.7,128.3, 127.6, 126.6, 126.0, 125.8, 122.6, 66.4, 62.1, 36.3, 14.0;HRMS(ESI) calcd for C₂₄H₂₃N₂O₄ (M+H)⁺: 403.1658, Found: 403.1659; 97:3e.r. as determined by HPLC [Chiralcel IA, 90:10 hexanes/i-PrOH, 0.7mL/min)], t_(r) (major)=93.4 min, t_(r) (minor)=78.9 min.

Example 52: (2R,3R)-ethyl1-benzamido-3-(furan-2-yl)-5-oxopyrrolidine-2-carboxylate: colorlessoil; [α]_(D) ²³ (c 1.55, CH₂Cl₂)=−40.8°; ¹H NMR (400 MHz, CDCl₃) δ=1.26(t, J=7.2 Hz, 3H), 2.80-2.95 (m, 2H), 3.74 (dd, J=15.2 Hz, 7.2 Hz, 1H),4.19-4.31 (m, 2H), 4.80 (d, J=6.4 Hz, 1H), 6.36-6.39 (m, 2H), 7.43 (t,J=7.6 Hz, 3H), 7.53 (t, J=7.6 Hz, 1H), 7.83 (d, J=7.6 Hz, 2H), 8.48 (bs,1H); ¹³C NMR (100 MHz, CDCl₃) δ=172.1, 170.4, 165.8, 152.5, 142.4,132.6, 131.3, 128.7, 127.5, 110.6, 106.8, 64.7, 62.1, 34.4, 33.6, 14.1;HRMS(ESI) calcd for C₁₈H₁₉N₂O₅ (M+H)⁺: 343.1294, Found: 343.1295; 95:5e.r. as determined by HPLC [Chiralcel IA, 70:20:10hexanes/(hexanes:i-PrOH:CH₃OH=90:5:5)/i-PrOH, 0.7 mL/min)], t_(r)(major)=63.7 min, t_(r) (minor)=56.4 min.

Example 53:(2R,3S)-ethyl1-benzamido-3-(3-(cyclopentyloxy)-4-methoxyphenyl)-5-oxopyrrolidine-2-carboxylate:yellow oil; [α]_(D) ²³ (c 0.63, CH₂Cl₂)=−66.3°; ¹H NMR (400 MHz, CDCl₃)5=1.24 (t, J=7.2 Hz, 3H), 1.61-1.63 (m, 2H), 1.86-2.02 (m, 6H), 2.63(dd, J=17.2 Hz, 6.0 Hz, 1H), 2.99 (dd, J=17.2, 6.0 Hz, 1H), 3.48-3.53(m, 1H), 3.85 (s, 3H), 4.18-4.29 (m, 2H), 4.69 (d, J=4.8 Hz, 1H),4.90-4.92 (m, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 7.06(s, 1H), 7.46 (t, J=7.6 Hz, 2H), 7.56 (t, J=7.6 Hz, 1H), 7.84 (d, J=7.2Hz, 2H), 8.28 (bs, 1H); ¹³C NMR (100 MHz, CDCl₃) δ=173.1, 171.0, 166.1,150.7, 147.3, 134.2, 132.5, 128.6, 127.6, 119.3, 115.1, 110.7, 80.6,67.5, 51.9, 56.4, 40.2, 36.9, 32.9, 24.1, 14.2, HRMS(ESI) calcd forC₂₆H₃₁N₂O₆ (M+H)⁺: 467.2182, Found: 467.2813; 96:4 e.r. as determined byHPLC (Chiralcel IA, 93:7 hexanes/i-PrOH, 0.7 mL/min), t_(r) (major)=94.6min, t_(r) (minor)=73.1 min.

Example 54:(2R,3S)-ethyl1-(4-chlorobenzamido)-5-oxo-3-phenylpyrrolidine-2-carboxylate:white solid, trans:cis=7:1, 70% yield of both isomers; [α]_(D) ²³ (c1.25, CH₂Cl₂)=−26.8°. ¹H NMR (400 MHz, CDCl₃) δ=1.22 (t, J=7.2 Hz, 3H),2.72 (dd, J=17.6 Hz, 6.8 Hz, 1H), 3.09 (dd, J=17.6 Hz, 9.6 Hz, 1H),3.59-3.64 (m, 1H), 4.15-4.28 (m, 2H), 4.70 (d, J=5.6 Hz, 1H), 7.32-7.48(m, 7H), 7.77 (d, J=8.8 Hz, 2H), 9.19 (bs, 1H); ¹³C NMR (100 MHz, CDCl₃)δ=173.4, 170.8, 164.9, 141.2, 129.2, 129.0, 128.9, 127.8, 127.2, 67.3,61.9, 40.6, 36.8, 14.1; HRMS(ESI) calcd for C₂₀H₂₀N₂O₄Cl (M+H)⁺:387.1112, Found: 387.1111; 96:4 e.r. as determined by HPLC [ChiralcelIA, 73:20:7 hexanes/(hexanes:i-PrOH:CH₃OH=90:5:5)/i-PrOH, 0.7 mL/min)],t_(r) (major)=125.9 min, t_(r) (minor)=100.0 min.

Example 55: (2R,3S)-ethyl1-(4-fluorobenzamido)-5-oxo-3-phenylpyrrolidine-2-carboxylate: Whitesolid, trans:cis=5:1, 61% yield of both isomers; [α]_(D) ²³(c 1.0,CHCl₃)=−59.6; ¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 7.89-7.86 (m, 2H),7.50-7.40 (m, 4H), 7.35-7.27 (m, 1H), 7.09-7.01 (m, 2H), 4.72 (d, J=5.6Hz, 1H), 4.36-4.10 (m, 2H), 3.65-3.60 (m, 1H), 3.10 (dd, J=17.6, 10.0Hz, 1H), 2.93 (dd, J=17.2, 6.4 Hz, 1H), 1.22 (t, J=7.2, 3H); ¹³C NMR(100 MHz, CDCl₃) δ 173.6, 171.0, 166.8, 165.0, 164.3, 141.5, 130.3 (d,J=9.0 Hz), 129.3, 128.0, 127.5 (d, J=13.0 Hz), 116.0 (d, J=22.0 Hz),69.6, 62.1, 40.8, 37.0. 14.3; HRMS for C₂₀H₂₀N₂O₄ [M+1]⁺ Calculated:371.1407, Found: 371.1398; 96:4 e.r. as determined by HPLC [ChiralcelIA, 75:20:5 hexanes/(hexanes:i-PrOH:CH₃OH=90:5:5)/i-PrOH, 0.7 mL/min)],t_(r) (major)=146.8 min, t_(r) (minor)=111.6 min.

Example 56: (2R,3S)-ethyl1-(3-bromobenzamido)-5-oxo-3-phenylpyrrolidine-2-carboxylate: Whitesolid, trans:cis=5:1, 59% yield of both isomers; [α]_(D) ²³ (c 1.1,CHCl₃)=−45.3; ¹H NMR (400 MHz, CDCl₃) δ 9.09 (s, 1H), 7.97 (s, 1H), 7.77(d, J=8.0 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.47 (d, J=7.6 Hz, 2H), 7.40(t, J=7.6 Hz, 2H), 7.34-7.26 (m, 2H), 4.71 (d, J=5.6 Hz, 1H), 4.31-4.09(m, 2H), 3.63-3.58 (m, 1H), 3.06 (dd, J=17.2, 9.6 Hz, 1H), 2.70 (dd,J=17.6, 6.8 Hz, 1H), 1.22 (t, J=7.2, 3H); ¹³C NMR (100 MHz, CDCl₃) δ173.3, 171.0, 164.7, 141.5, 135.6, 133.2, 131.1, 130.4, 129.3, 127.9,127.4, 126.2, 123.1, 67.4, 62.2, 40.8, 36.9, 14.3; HRMS for C₂₀H₂₀N₂O₄Br[M+1]⁺ Calculated: 431.0606, Found: 431.0609; HPLC analysis: 96:4 e.r.as determined by HPLC [Chiralcel IA, 75:20:5hexanes/(hexanes:i-PrOH:CH₃OH=90:5:5)/i-PrOH, 0.7 mL/min)], t_(r)(major)=47.4 min, t_(r) (minor)=52.9 min.

Example 57: (2R,3S)-ethyl1-(4-methoxybenzamido)-5-oxo-3-phenylpyrrolidine-2-carboxylate: Whitesolid, trans cis=5:1, 70% yield of both isomers; [α]_(D) ²³ (c 0.3,CHCl₃)=−58.3; ¹H NMR (400 MHz, CDCl₃) δ 8.44 (s, 1H), 7.81-7.79 (m, 2H),7.47 (d, J=7.6 Hz, 2H), 7.39 (t, J=7.2 Hz, 2H), 7.32-7.25 (m, 1H),6.93-6.88 (m, 2H), 4.71 (d, J=5.6 Hz, 1H), 4.29-4.10 (m, 2H), 3.84 (s,3H), 3.59-3.54 (m, 1H), 3.02 (dd, J=17.6, 10.0 Hz, 1H), 2.67 (dd,J=17.6, 6.8 Hz, 1H), 1.20 (t, J=7.2, 3H); ¹³C NMR (100 MHz, CDCl₃) δ173.0, 171.2, 165.8, 163.3, 141.7, 129.7, 129.3, 127.9, 127.4, 123.8,114.2, 67.5, 62.1, 55.7, 40.8, 37.0, 14.4; HRMS for C₂₁H₂₃N₂O₅ [M+1]⁺Calculated: 383.1607, Found: 383.1637; HPLC analysis: 97:3 e.r. asdetermined by HPLC [Chiralcel IA, 65:30:5hexanes/(hexanes:i-PrOH:CH₃OH=90:5:5)/i-PrOH, 0.7 mL/min)], t_(r)(major)=96.6 min, t_(r) (minor)=103.0 min.

Example 58: (2R,3S)-ethyl1-(4-bromobenzamido)-5-oxo-3-phenylpyrrolidine-2-carboxylate: Whitesolid, trans:cis=5:1, 65% yield of both isomers; [α]_(D) ²³ (c 0.2,CHCl₃)=−10; ¹H NMR (400 MHz, CDCl₃) δ 8.91 (s, 1H), 7.68 (d, J=8.4 Hz,2H), 7.53 (d, J=8.4 Hz, 2H), 7.46 (d, J=7.6 Hz, 2H), 7.39-7.25 (m, 3H),4.69 (d, J=5.6 Hz, 1H), 4.29-4.10 (m, 2H), 3.62-3.56 (m, 1H), 3.05 (dd,J=17.6, 9.6 Hz, 1H), 2.69 (dd, J=17.6, 6.4 Hz, 1H), 1.21 (t, J=7.2, 3H);¹³C NMR (100 MHz, CDCl₃) δ 173.2, 171.0, 165.3, 141.5, 132.2, 130.2,129.4, 129.3, 128.0, 127.7, 127.4, 67.5, 62.2, 40.8, 36.9, 14.3; HRMSfor C₂₀H₂₀N₂O₄Br [M+1]⁺ Calculated: 431.0606, Found: 431.0626; 95:5 e.r.as determined by HPLC [Chiralcel IA, 65:30:5hexanes/(hexanes:i-PrOH:CH₃OH=90:5:5)/i-PrOH, 0.7 mL/min)], t_(r)(major)=66.1 min, t_(r) (minor)=60.0 min.

Example 59: (2R,3S)-ethyl1-(1-naphthamido)-5-oxo-3-phenylpyrrolidine-2-carboxylate: White solid,trans:cis=6:1, 71% yield of both isomers; [α]_(D) ²³ (c 0.9, CHCl₃)=−15;¹H NMR (400 MHz, CDCl₃) δ 8.48 (d, J=8.0 Hz, 1H), 8.00 (d, J=8.0 Hz,1H), 7.90 (d, J=7.6 Hz, 1H), 7.79 (d, J=6.8 Hz 1H), 7.62-7.41 (m, 7H),7.36-7.34 (m, 1H), 4.85 (d, J=5.6 Hz, 1H), 4.29-4.18 (m, 2H), 3.65-3.59(m, 2H), 3.03 (dd, J=17.6, 8.0 Hz, 1H), 2.74 (dd, J=17.6, 6.8 Hz, 1H),1.24 (t, J=7.2 Hz, 3H); ¹³C NMR (mixture of both isomers, 100 MHz,CDCl₃) δ 172.6, 171.1, 168.3, 141.5, 133.9, 132.1, 130.7, 130.5, 129.4,128.7, 128.6, 128.0, 127.8, 127.4, 127.0, 126.4, 125.5, 125.2, 124.8,124.7, 67.5, 62.2, 62.0, 40.9, 36.9. 14.4; HRMS for C₂₄H₂₃N₂O₄ [M+1]⁺Calculated: 403.1658, Found: 403.1643; 95:5 e.r. as determined by HPLC[Chiralcel IA, 75:20:5 hexanes/(hexanes:i-PrOH:CH₃OH=90:5:5)/i-PrOH, 0.7mL/min)], t_(r) (major)=107.2 min, t_(r) (minor)=120.6 min.

Example 60: (2R,3S)-ethyl3-(4-chlorophenyl)-5-oxopyrrolidine-2-carboxylate: yellow oil; [α]_(D)²³ (c 0.67, CH₂Cl₂)=−66.6°; ¹H NMR (400 MHz, CDCl₃) δ=1.27 (t, J=7.2 Hz,3H), 2.49 (dd, J=17.6 Hz, 6.8 Hz, 1H), 2.86 (dd, J=17.2, 9.6 Hz, 1H),3.68-3.74 (m, 1H), 4.17-4.27 (m, 3H), 6.14 (bs, 1H), 7.23 (d, J=8.0 Hz,2H), 7.34 (d, J=8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ=176.6, 171.1,140.3, 133.3, 129.2, 128.4, 62.9, 61.9, 43.3, 38.0, 14.1; HRMS(ESI)calcd for C₁₃H₁₅NO₃Cl (M+H)⁺: 268.0740, Found: 268.0743; 96:4 e.r. asdetermined by HPLC [Chiralcel IB, 95:5 hexanes/i-PrOH, 0.7 mL/min)],t_(r) (major)=60.4 min, t_(r) (minor)=53.8 min.

Example 61:(2R,3S)-ethyl3-(3-(cyclopentyloxy)-4-methoxyphenyl)-5-oxopyrrolidine-2-carboxylate:yellow oil; [α]_(D) ²³ (c 1.42, CH₂Cl₂)=−38.2°; ¹H NMR (400 MHz, CDCl₃)δ=1.27 (d, J=7.2 Hz, 3H), 1.60-1.66 (m, 2H), 1.81-1.92 (m, 6H), 2.51(dd, J=17.2 Hz, 6.4 Hz, 1H), 2.84 (dd, J=17.2, 6.4 Hz, 1H), 3.62-3.68(m, 1H), 3.84 (s, 3H), 4.18-4.27 (m, 3H), 4.75-4.78 (m, 1H), 6.17 (bs,1H), 6.80-6.85 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ=176.4, 171.3, 149.5,148.0, 134.3, 119.0, 113.8, 112.3, 80.6, 63.1, 61.8, 56.1, 43.5, 37.9,32.8, 24.0, 14.2; HRMS(ESI) calcd for C₁₉H₂₆NO₅ (M+H)⁺: 348.1811, Found:348.1813; 96:4 e.r. as determined by HPLC [Chiralcel IA, 90:10hexanes/i-PrOH, 0.7 mL/min)], t_(r) (major)=28.2 min, t_(r) (minor)=24.6min.

Example 62:(4S,5R)-4-(3-(cyclopentyloxy)-4-methoxyphenyl)-5-(hydroxymethyl)pyrrolidin-2-one:colorless oil; [α]_(D) ²³ (c 0.52, CH₂Cl₂)=−14.6°; ¹H NMR (400 MHz,CDCl₃) δ=1.59 (dd, J=7.0, 5.1 Hz, 2H), 2.02-1.69 (m, 6H), 2.53 (dd,J=17.2, 8.8 Hz, 1H), 2.77 (dd, J=17.2, 9.3 Hz, 1H), 3.36-3.12 (m, 1H),3.50-3.55 (m, 1H), 3.76 (d, J=7.3 Hz, 2H), 3.81 (s, 3H), 4.14 (brs, 1H),4.76 (dd, J=5.9, 2.7 Hz, 1H), 6.86-6.60 (m, 3H), 7.46 (brs, 1H); ¹³C NMR(100 MHz, CDCl₃) δ=24.0, 32.79, 32.82, 39.4, 42.0, 56.2, 64.0, 64.4,80.6, 112.3, 114.3, 119.3, 133.9, 147.9, 149.3, 178.0; HRMS(ESI) calcdfor C₁₇H₂₄NO₄ (M+H)⁺: 306.1705, Found: 306.1705.

Example 63:(2R,3S)-tert-butyl3-(3-(cyclopentyloxy)-4methoxyphenyl)-2-(hydroxymethyl)-5-oxopyrrolidine-1-carboxylate:colorless oil; [α]_(D) ²³ (c 0.4, CH₂Cl₂)=−8.5°; ¹H NMR (500 MHz, CDCl₃)δ=1.48 (s, 9H), 1.60-1.63 (m, 2H), 1.82-1.94 (m, 6H), 2.53 (dd, J=17.3,9.0 Hz, 1H), 2.79 (dd, J=17.3, 9.3 Hz, 1H), 3.22 (dd, J=16.5, 9.0 Hz,1H), 3.83 (s, 3H), 3.85-3.87 (m, 1H), 3.94 (dd, J=11.0, 6.0 Hz, 1H),4.25 (dd, J=11.5, 3.0 Hz, 1H), 4.76-4.78 (m, 1H), 6.77 (dd, J=12.0, 2.0Hz, 2H), 6.82 (d, J=8.5 Hz, 1H); ¹³CNMR (125 Hz, CDCl₃): δ=24.0, 27.7,32.8, 38.7, 42.6, 56.1, 60.8, 68.0, 80.6, 82.9, 112.3, 113.9, 119.3,133.1, 148.1, 149.5, 153.3, 176.2; HRMS(ESI) calcd for C₂₂H₃₂NO₆ (M+H)⁺:406.2230, Found: 406.2236. 96:4 e.r. as determined by HPLC [ChiralcelIA, 90:10 hexanes/i-PrOH, 0.7 mL/min)], t_(r) (major)=15.7 min, t_(r)(minor)=11.3 min.

While particular preferred and alternative embodiments of the presentinvention have been disclosed, it will be apparent to one of ordinaryskill in the art that many various modifications and extensions of theabove described technology may be implemented using the teaching of thisinvention described herein. All such modifications and extensions areintended to be included within the true spirit and scope of theinvention as discussed in the appended claims.

REFERENCES

-   1. Reed, P. E. & Katzenellenbogen, J. A. Beta-Substituted    Beta-Phenylpropionyl Chymotrypsins-Structural and Stereochemical    Features in Stable Acyl Enzymes. J. Med. Chem. 1991, 34, 1162-1176.-   2. Kerr, M. S., de Alaniz, J. R. & Rovis, T. An efficient synthesis    of achiral and chiral 1,2,4-triazolium salts: Bench stable    precursors for N-heterocyclic carbenes. J. Org. Chem. 2005, 70,    5725-5728.-   3. Matsuoka, Y., Ishida, Y., Sasaki, D. & Saigo, K. Cyclophane-Type    Imidazolium Salts with Planar Chirality as a New Class of    N-Heterocyclic Carbene Precursors. Chem.-Eur. J. 2008, 14,    9215-9222.-   4. Raup, D. E. A., Cardinal-David, B., Holte, D., Scheidt, K. A.    Cooperative Catalysis by Carbenes and Lewis Acids in a Highly    Stereoselective Route to β-Lactams.Nat. Chem. 2010, 2, 766-771.-   5. Oba, M., Saegusa, T., Nishiyama, N. & Nishiyama, K. Synthesis of    non-proteinogenic amino acids using Michael addition to unsaturated    orthopyroglutamate derivative. Tetrahedron 2009, 65, 128-133.-   6. Diaz, A. et al., A stereoselective synthesis of (R)-(-)-rolipram    from L-glutamic acid. Synthesis, 1997, 559-562.-   7. Chiang, P., Kaeobamrung, J. & Bode, J. W. Enantioselective,    cyclopentene-forming annulations via NHC-catalyzed benzoin-oxy-Cope    reactions. J. Am. Chem. Soc. 2007, 129, 3520-3521.

The invention claimed is:
 1. A method for synthesizing a compound ofFormula (Ia)

wherein n is 2; R₁ is 2-furyl, propyl, methyl, phenyl, p-tolyl,p-anisyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, or naphthyl, R₂is hydrogen; B is

wherein R₇ is phenyl, p-tolyl, p-chlorophenyl, p-bromophenyl, naphthyl,2-thiofuryl, o-nitrophenyl, m-nitrophenyl, or p-nitrophenyl, wherein R₈is phenyl, 2-furyl, p-tolyl, p-chlorophenyl or p-bromophenyl, wherein Aris phenyl, p-tolyl, p-chlorophenyl, p-bromophenyl, or 2-thiofuryl; andNHC^(⊕) is

comprising: (i) activating a compound of Formula (IIa)

wherein LG is —O—C₆H₄-para-NO₂; by reacting said compound of Formula(IIa) with one of the compounds of Formula (III) in the presence of DBU(1,8-Diazabicyclo[5.4.0]undec-7-en)

to obtain a compound of Formula (IVa)

and (ii) reacting the compound of Formula (IVa) with an electrophile toobtain the compound of Formula (Ia), wherein the electrophile isselected from the group consisting of


2. The method according to claim 1, wherein NHC^(⊕) is selected from thegroup consisting of


3. The method according to claim 2, wherein NHC^(⊕) is selected from thegroup consisting of


4. The method according to claim 1, wherein NHC^(⊕) is selected from thegroup consisting of


5. The method according to claim 1, wherein the compound of Formula(III) is synthesized from any of the following compounds selected fromthe group consisting of

wherein X is BF₄ ⁻.
 6. The method according to claim 1, wherein thecompound of Formula (III) is generated in situ from any of the followingcompounds selected from the group consisting of

wherein X is BF₄ ⁻


7. The method according to claim 1, wherein the method is carried out ina solvent selected from the group consisting of tent-Butanol, toluene,THF, CH₃CN, CH₂Cl₂, dioxane, and ethyl acetate.
 8. The method accordingto claim 1, wherein the reaction temperature of steps (i) and (ii) is25° C. or 40° C.
 9. The method according to claim 1, wherein thereaction time is about 24 hours.
 10. The method according to claim 1,wherein a molecular sieve is present during the reaction.
 11. The methodaccording to claim 10, wherein the molecular sieve has apertures of asize of approximately 4 Å.
 12. The method according to claim 1, whereinthe method comprises further reaction steps selected from catalystregeneration, michael reaction, aldol reaction, lactonization, and/ordecarboxylation.